Pyridyl benzothiophenes as kinase inhibitors

ABSTRACT

This invention is directed to compounds, which are useful as protein kinase (PK) inhibitors and can be used to treat such diseases as cancer, blood vessel proliferative disorders, fibrotic disorders, mesangial cell proliferative disorders, metabolic diseases inflammatory disorders and neurodegenerative disorders.

CROSS-RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/511,112, filed Oct. 9, 2014, the disclosure of which is herebyincorporated by reference in its entirety and serves as the basis of apriority and/or benefit claim for the present application.

FIELD OF THE INVENTION

The invention relates to inhibitors of VEGFR2 kinase or VEGFR, PDGFRkinases or PDGFR and Protein Kinase R (EIF2AK2), and methods of usingsuch compounds. The present invention is also directed to methods ofregulating, modulating or inhibiting protein kinases, whether of thereceptor or non-receptor class, for the prevention and/or treatment ofdisorders related to unregulated protein kinase signal transduction,including cell growth, metabolic, and blood vessel proliferativedisorders.

DESCRIPTION OF THE RELATED ART

Protein kinases (PKs) comprise a large and diverse class of proteinshaving enzymatic activity which catalyzes the transfer of the terminalphosphate of ATP to the hydroxyl group of a serine, threonine ortyrosine group in a protein. Protein kinases (PKs) are involved innumerous diseases which result from dysregulation of their normalfunction.

There are numerous examples where protein kinases, have been found to beinvolved in cellular signaling pathways leading to pathologicalconditions. In the VEGFR2 kinase protein kinase, which is a receptortyrosine kinase, pathological conditions involving aberrant angiogenesisinclude cancer, wet age-related macular degeneration (Ni et al.Opthalmologica 2009 223 401-410; Chappelow et al. Drugs 2008 681029-1036), diabetic retinopathy (Zhang et al Int. J. Biochem. CellBiol. 2009 41 2368-2371), cancer (Aora et al. J. Path. Exp. Ther. 2006,315, 971), psoriasis (Heidenreich et al Drug News Perspective 2008 2197-105) and hyper immune response. In ophthalmic diseases such asneovascular age-related macular degeneration and diabetic retinopathyaberrant activation of VEGF receptors can lead to abnormal blood vesselgrowth. The importance of VEGFR signaling in the neovascular age-relatedmacular degeneration disease process is evident by the clinical successof multiple anti-VEGF targeting agents including Lucentis®, Avastin®,and EYLEA™ (Barakat et al. Expert Opin. Investig. Drugs 2009, 18, 637).Recently it has been suggested that inhibition of multiple proteinkinase signaling pathways may provide a greater therapeutic effect thantargeting a single signaling pathway. For example in neovascular oculardisorders such as neovascular age-related macular degeneration anddiabetic retinopathy the inhibition of both VEGFR and PDGFRβ may providea greater therapeutic effect in by causing regression of existingneovascular blood vessels present in the disease (Adamis et al. Am. J.Pathol. 2006 168 2036-2053). In cancer inhibition of multiple PKsignaling pathways has been suggested to have a greater effect thaninhibiting a single PK pathway (DePinho et al. Science 2007 318 287-290;Bergers et al. J. Clin Invest. 2003 111 1287-1295).

It has also been suggested that misregulated protein kinases areinvolved in neurodegenerative disease. In particular Protein Kinase Rhas been implicated in neurodegenerative disease. Protein Kinase R (PKR,also known as interferon-induced, double-stranded RNA-activated proteinkinase, or eukaryotic translation initiation factor 2-alpha kinase 2) isone of four known mammalian kinases that phosphorylate eukaryotictranslation initiation factor 2-alpha (eIF-2α) in response to a varietyof stress conditions (Donnelly et al., Cell. Mol. Life Sci. 2013, 70,3493-3511). PKR plays a central role in the innate immune system andserves to prevent viral replication and viral infection (for a detailedreview see Garcia et al., Microbiol. and Mol. Bio. Rev. 2006, 70,1032-1060). It is proposed that in chronic conditions like AMD, innateimmune players respond to modified host derived elements (ROS/Alu) andexternal particulate matter (drusen) by activation of inflammasomecomplex. Emerging evidence indicates that PKR has a key role in NLRP3inflammasome activation (Yim & Williams; J of Interferon & Cytokine Res,2014, Campbell & Doyle, J Mol Med, 2013, Lu et. al; Nature, 2012).

The binding of double stranded RNA to the double stranded RNA regulatorydomains of PKR induces dimerization and autophosphorylation which leadsto activation of the kinase (Dever et al., Cell 2005, 122, 901-913).Once activated by dimerization PKR can suppress protein synthesis byphosphorylation of serine-51 on eukaryotic translation initiation factor2-alpha (eIF-2α). In its phosphorylated form eIF2alpha increases itsaffinity for eIF-2B by 100-fold effectively converting it into acompetitive inhibitor of eIF-2B. By this mechanism a small amount ofphosphorylated eIF2alpha can effectively inhibit the guanine nucleotideexchange activity of eIF-2B and shut down protein translation (Ramaiahet al., Biochemistry 2000, 39, 12929-12938).

In addition to PKR's role in regulation of protein synthesis it alsoplays an important role in signal transduction linked to apoptotic celldeath. PKR has been shown to be activated by dsRNA, number of growthfactors and cytokines including INF, PDGF, TNF-alpha, and IL-1 and bythe activation of Toll receptors. PKR has also been shown to bephosphorylated by JAK1 and Tyk2 kinases (Su et al., EMBO Reports 2007,3, 265). Activation of PKR leads to the activation of multiple signalingpathways that are involved in inflammation and cell death. PKR isrequired for phosphorylation of MKK6 (Williams et al., J. Biol. Chem.2004, 279, 37670-37676) and subsequent p38 MAPK signaling (Williams etal., The EMBO Journal 2000, 19, 4292-4297). PKR induces the expressionof the pro apoptotic factor CHOP and has been shown to induce apoptosisby the FADD/Caspase 8 pathway (Barber, G. et al, The EMBO Journal 1998,17, 6888-6902).

Due to its key role in regulation of apoptotic cell death PKR inhibitionmay be useful in prevention of the rod and cone photoreceptor cell deathand ganglion cell death associated with the atrophic form of maculardegeneration (Shimazawa et al, IVOS 2007, 48, 3729-3736).

The identification of effective small compounds which specificallyinhibit signal transduction by modulating the activity of receptor andnon-receptor protein kinases to regulate and modulate abnormal orinappropriate cell proliferation is therefore desirable and one objectof this invention.

Certain small compounds are disclosed in PCT publication No.WO/1999/062890, PCT publication No. WO/2005/082001 and PCT publicationNo. WO/2006/026034 as useful for the treatment of diseases related tounregulated TKS transduction. These patents disclose starting materialsand methods for the preparation thereof, screens and assays to determinea claimed compound's ability to modulate, regulate and/or inhibit cellproliferation, indications which are treatable with said compounds,formulations and routes of administration, effective dosages, etc.

US2009/0163545 refers to methods of using lifespan-altering compoundsfor altering the lifespan of eukaryotic organisms and screening for suchcompounds.

WO2009/019504 refers to the preparation of benzoxazoles, benzimidazoles,indoles and their analogs for the treatment of muscular dystrophy andcachexia.

WO2007/091106 refers to the preparation of benzoxazoles, benzimidazoles,indoles and their analogs for the treatment of muscular dystrophy andcachexia.

KR 2011033395 refers to the preparation of benzoxazolyl-pyridinederivatives as protein kinase inhibitors.

WO2009/075874 refers to the preparation of N-[4-pyridin-4-yl)phenyl]amides as gamma-secretase modulators.

SUMMARY OF THE INVENTION

The present invention relates to organic molecules capable ofmodulating, regulating and/or inhibiting protein kinase signaltransduction, useful for treating diseases related to protein kinasesignal transduction, for example, cancer, blood vessel proliferativedisorders, fibrotic disorders, and neurodegenerative diseases. Inparticular, the compounds of the present invention are useful fortreatment of mesangial cell proliferative disorders and metabolicdiseases, lung carcinomas, breast carcinomas, Non Hodgkin's lymphomas,ovarian carcinoma, pancreatic cancer, malignant pleural mesothelioma,melanoma, arthritis, restenosis, hepatic cirrhosis, atherosclerosis,psoriasis, rosacea, diabetic mellitus, wound healing, inflammation andneurodegenerative diseases and preferably ophthalmic diseases, i.e.diabetic retinopathy, retinopathy of prematurity, macular edema, retinalvein occlusion, exudative or neovascular age-related maculardegeneration, high-risk eyes (i.e. fellow eyes have neovascularage-related macular degeneration) with dry age-related maculardegeneration, neovascular disease associated with retinal veinocclusion, neovascular disease (including choroidal neovascularization)associated with the following: pathologic myopia, pseudoxanthomaelasticum, optic nerve drusen, traumatic choroidal rupture, atrophicmacular degeneration, geographic atrophy, central serous retinopathy,cystoid macular edema, diabetic retinopathy, proliferative diabeticretinopathy, diabetic macular edema, rubeosis iridis, retinopathy ofprematurity, Central and branch retinal vein occlusions,inflammatory/infectious retinal, neovascularization/edema, cornealneovascularization, hyperemia related to an actively inflamed pterygia,recurrent pterygia following excisional surgery, post-excision,progressive pterygia approaching the visual axis, prophylactic therapyto prevent recurrent pterygia, of post-excision, progressive pterygiaapproaching the visual axis, chronic low grade hyperemia associated withpterygia, neovascular glaucoma, iris neovascularization, idiopathicetiologies, presumed ocular histoplasmosis syndrome, retinopathy ofprematurity, chronic allergic conjunctivitis, ocular rosacea,blepharoconjunctivitis, recurrent episcleritis, keratoconjunctivitissicca, ocular graft vs host disease, etc.

In one aspect, the invention provides a compound represented by FormulaI or a pharmaceutically acceptable salt thereof or stereoisomeric formsthereof, or the enantiomers, diastereoisomers, tautomers, zwitterionsand pharmaceutically acceptable salts thereof:

wherein:

W is O, S, N(CO)R¹⁴, CF₂, C(CH₃)₂, N(CO)(NH)R¹⁴ or NR¹⁴;

R¹ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, halo orhaloalkyl;

R² is —N(R⁴)C(O)N(R⁴R⁵), —N(R⁴)C(O)R⁵, —C(O)N(R⁴R⁵), hydrogen,substituted or unsubstituted C₁₋₈ alkyl, halo or haloalkyl;

R³ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, halo orhaloalkyl;

X is —N(R⁴)C(O)N(R⁴R⁵), —N(R⁴)C(O)R⁵, —C(O)N(R⁴R⁵), hydrogen,substituted or unsubstituted C₁₋₈ alkyl, halo or haloalkyl;

R⁴ is hydrogen or substituted or unsubstituted alkyl;

R⁵ is substituted or unsubstituted alkyl, substituted or unsubstitutedheterocycle or substituted or unsubstituted aryl;

Y is hydrogen, —C(O)—N═S(O)R⁷R⁶, —N(R⁴)C(O)R⁸, —COOR⁹, —C(O)NHR¹⁰,—B(OH)₂, —B(OR¹²)(OR¹³) or

R⁷ is substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted heterocycle or substituted or unsubstituted aryl;

R⁶ is substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted heterocycle or substituted or unsubstituted aryl;

R⁸ is substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted heterocycle or substituted or unsubstituted aryl;

R⁹ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted heterocycle or substituted or unsubstituted aryl;

R¹⁰ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted heterocycle or substituted or unsubstituted aryl;

Z is —NHR¹¹;

R¹¹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;

R¹² is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;

R¹³ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;

R¹⁴ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl; and

with the proviso that the compound of Formula I is not

In another aspect, the invention provides a compound represented byFormula I wherein:

W is O, S, N(CO)R¹⁴, CF₂, C(CH₃)₂, N(CO)(NH)R¹⁴ or NR¹⁴;

R¹ is hydrogen;

R² is hydrogen;

R³ is hydrogen;

X is —N(R⁴)C(O)N(R⁴R⁵), —N(R⁴)C(O)R⁵, or —C(O)N(R⁴R⁵);

R⁴ is hydrogen or substituted or unsubstituted alkyl;

R⁵ is substituted or unsubstituted alkyl, substituted or unsubstitutedheterocycle or substituted or unsubstituted aryl;

Y is hydrogen, —C(O)—N═S(O)R⁷R⁶, —COOR⁹, —C(O)NHR¹⁰, —B(OH)₂, or

R⁷ is substituted or unsubstituted C₁₋₈ alkyl;

R⁶ is substituted or unsubstituted C₁₋₈ alkyl;

R⁹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;

R¹⁰ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;

Z is —NHR¹¹; and

R¹¹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;

R¹⁴ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl; and

with the proviso that the compound of Formula I is not

In another aspect, the invention provides a compound represented byFormula I wherein:

W is S;

R¹ is hydrogen;

R² is hydrogen;

R³ is hydrogen;

X is —N(R⁴)C(O)N(R⁴R⁵);

R⁴ is hydrogen or substituted or unsubstituted alkyl;

R⁵ is substituted or unsubstituted alkyl, substituted or unsubstitutedheterocycle or substituted or unsubstituted aryl;

Y is hydrogen, —C(O)—N═S(O)R⁷R⁶, —COOR⁹, —C(O)NHR¹⁰, —B(OH)₂, or

R⁷ is substituted or unsubstituted C₁₋₈ alkyl;

R⁶ is substituted or unsubstituted C₁₋₈ alkyl;

R⁹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;

R¹⁰ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;

Z is —NHR¹¹; and

R¹¹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl.

In another aspect, the invention provides a compound represented byFormula I wherein:

W is S;

R¹ is hydrogen;

R² is hydrogen;

R³ is hydrogen;

X is —N(R⁴)C(O)N(R⁴R⁵);

R⁴ is hydrogen or substituted or unsubstituted alkyl;

R⁵ is substituted or unsubstituted alkyl, substituted or unsubstitutedheterocycle or substituted or unsubstituted aryl;

Y is —C(O)—N═S(O)R⁷R⁶;

R⁷ is substituted or unsubstituted C₁₋₈ alkyl;

R⁶ is substituted or unsubstituted C₁₋₈ alkyl;

Z is —NHR¹¹; and

R¹¹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl.

In another aspect, the invention provides a compound represented byFormula I wherein:

W is S;

R¹ is hydrogen;

R² is hydrogen;

R³ is hydrogen;

X is —N(R⁴)C(O)N(R⁴R⁵);

R⁴ is hydrogen or substituted or unsubstituted alkyl;

R⁵ is substituted or unsubstituted alkyl, substituted or unsubstitutedheterocycle or substituted or unsubstituted aryl;

Y is —C(O)—N═S(O)R⁷R⁶;

R⁷ is substituted or unsubstituted C₁₋₈ alkyl;

R⁶ is substituted or unsubstituted C₁₋₈ alkyl;

Z is —NHR¹¹; and

R¹¹ is hydrogen.

In another aspect, the invention provides a compound represented byFormula I wherein:

W is S;

R¹ is hydrogen;

R² is hydrogen;

R³ is hydrogen;

X is —N(R⁴)C(O)N(R⁴R⁵);

R⁴ is hydrogen;

R⁵ is substituted or unsubstituted alkyl, substituted or unsubstitutedheterocycle or substituted or unsubstituted aryl;

Y is —C(O)—N═S(O)R⁷R⁶;

R⁷ is substituted or unsubstituted C₁₋₈ alkyl;

R⁶ is substituted or unsubstituted C₁₋₈ alkyl;

Z is —NHR¹¹; and

R¹¹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl.

In another aspect, the invention provides a compound represented byFormula I wherein:

W is S;

R¹ is hydrogen;

R² is hydrogen;

R³ is hydrogen;

X is —N(R⁴)C(O)N(R⁴R⁵);

R⁴ is hydrogen;

R⁵ is substituted or unsubstituted aryl;

Y is —C(O)—N═S(O)R⁷R⁶;

R⁷ is substituted or unsubstituted C₁₋₈ alkyl;

R⁶ is substituted or unsubstituted C₁₋₈ alkyl;

Z is —NHR¹¹; and

R¹¹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl.

In another aspect, the invention provides a compound represented byFormula I wherein:

W is S;

R¹ is hydrogen;

R² is hydrogen;

R³ is hydrogen;

X is —N(R⁴)C(O)N(R⁴R⁵);

R⁴ is hydrogen;

R⁵ is substituted or unsubstituted heterocycle;

Y is —C(O)—N═S(O)R⁷R⁶;

R⁷ is substituted or unsubstituted C₁₋₈ alkyl;

R⁶ is substituted or unsubstituted C₁₋₈ alkyl;

Z is —NHR¹¹; and

R¹¹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl.

In another aspect, the invention provides a compound represented byFormula I wherein:

W is S;

R¹ is hydrogen;

R² is hydrogen;

R³ is hydrogen;

X is —N(R⁴)C(O)R⁵;

R⁴ is hydrogen;

R⁵ is substituted or unsubstituted heterocycle or substituted orunsubstituted aryl;

Y is hydrogen, —C(O)—N═S(O)R⁷R⁶, —COOR⁹, —C(O)NHR¹⁰, —B(OH)₂, or

R⁷ is substituted or unsubstituted C₁₋₈ alkyl;

R⁶ is substituted or unsubstituted C₁₋₈ alkyl;

R⁹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;

R¹⁰ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;

Z is —NHR¹¹; and

R¹¹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl.

In another aspect, the invention provides a compound represented byFormula I wherein:

W is S;

R¹ is hydrogen;

R² is hydrogen;

R³ is hydrogen;

X is —N(R⁴)C(O)R⁵;

R⁴ is hydrogen;

R⁵ is substituted or unsubstituted aryl;

Y is hydrogen, —C(O)—N═S(O)R⁷R⁶, —COOR⁹, —C(O)NHR¹⁰, —B(OH)₂, or

R⁷ is substituted or unsubstituted C₁₋₈ alkyl;

R⁶ is substituted or unsubstituted C₁₋₈ alkyl;

R⁹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;

R¹⁰ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;

Z is —NHR¹¹; and

R¹¹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl.

In another aspect, the invention provides a compound represented byFormula I wherein:

W is S;

R¹ is hydrogen;

R² is hydrogen;

R³ is hydrogen;

X is —C(O)N(R⁴R⁵);

R⁴ is hydrogen;

R⁵ is substituted or unsubstituted aryl;

Y is —COOR⁹;

R⁷ is substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted heterocycle or substituted or unsubstituted aryl;

R⁶ is substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted heterocycle or substituted or unsubstituted aryl;

R⁹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;

Z is —NHR¹¹; and

R¹¹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl.

In another aspect, the invention provides a compound represented byFormula I wherein:

W is S;

R¹ is hydrogen;

R² is hydrogen;

R³ is hydrogen;

X is —N(R⁴)C(O)N(R⁴R⁵);

R⁴ is hydrogen;

R⁵ is substituted or unsubstituted aryl;

Y is —C(O)NHR¹⁰;

R¹⁰ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;

Z is —NHR¹¹; and

R¹¹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl.

In another aspect, the invention provides a compound represented byFormula I wherein:

W is S;

R¹ is hydrogen;

R² is hydrogen;

R³ is hydrogen;

X is —N(R⁴)C(O)N(R⁴R⁵);

R⁴ is hydrogen;

R⁵ is substituted or unsubstituted aryl;

Y is

Z is —NHR¹¹; and

R¹¹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl.

In another aspect, the invention provides a compound represented byFormula I wherein:

W is S;

R¹ is hydrogen;

R² is hydrogen;

R³ is hydrogen;

X is —N(R⁴)C(O)N(R⁴R⁵);

R⁴ is hydrogen;

R⁵ is substituted or unsubstituted aryl;

Y is —B(OH)₂;

Z is —NHR¹¹; and

R¹¹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl.

In another aspect, the invention provides a compound represented byFormula I wherein:

W is S;

R¹ is hydrogen;

R² is hydrogen;

R³ is hydrogen;

X is —N(R⁴)C(O)R⁵;

R⁴ is hydrogen;

R⁵ is substituted or unsubstituted aryl;

Y is hydrogen;

Z is —NHR¹¹; and

R¹¹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl.

In another aspect, the invention provides a compound represented byFormula I wherein:

W is S;

R¹ is hydrogen;

R² is hydrogen;

R³ is hydrogen;

X is —C(O)N(R⁴R⁵);

R⁴ is hydrogen or substituted or unsubstituted alkyl;

R⁵ is substituted or unsubstituted alkyl or substituted or unsubstitutedheterocycle or substituted or unsubstituted aryl;

Y is hydrogen;

Z is —NHR¹¹; and

R¹¹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl.

In one aspect, the invention provides a compound represented by FormulaII or a pharmaceutically acceptable salt thereof or stereoisomeric formsthereof, or the enantiomers, diastereoisomers, tautomers, zwitterionsand pharmaceutically acceptable salts thereof:

wherein:

R¹⁵ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, halo orhaloalkyl;

R¹⁶ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, halo orhaloalkyl;

R¹⁷ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, halo orhaloalkyl;

X^(a) is —N(R¹⁹)C(O)N(R¹⁹R²⁰);

R¹⁸ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, halo orhaloalkyl;

R¹⁹ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted heterocycle or substituted or unsubstituted aryl;

R²⁰ is substituted or unsubstituted alkyl, substituted or unsubstitutedheterocycle or substituted or unsubstituted aryl;

Y^(a) is hydrogen, —C(O)—N═S(O)R²¹R²², —N(R²³)C(O)R²⁴, —COOR²⁵,—C(O)NHR²⁷, —B(OH)₂, —B(OR²⁸)(OR²⁹) or

R²¹ is substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted heterocycle or substituted or unsubstituted aryl;

R²² is substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted heterocycle or substituted or unsubstituted aryl;

R²³ is substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted heterocycle or substituted or unsubstituted aryl;

R²⁴ is hydrogen, substituted or unsubstituted C₁₋₈ alkyl, substituted orunsubstituted heterocycle or substituted or unsubstituted aryl;

Z^(a) is —NHR²⁶;

R²⁵ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;

R²⁶ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;

R²⁷ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl;

R²⁸ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl; and

R²⁹ is hydrogen or substituted or unsubstituted C₁₋₈ alkyl.

The term “alkyl”, as used herein, refers to saturated, monovalent ordivalent hydrocarbon moieties having linear or branched moieties orcombinations thereof and containing 1 to 12 carbon atoms. One methylene(—CH₂—) group, of the alkyl group can be replaced by oxygen, sulfur,sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate,amide, sulfonamide, by a divalent C₃₋₈ cycloalkyl, by a divalentheterocycle, or by a divalent aryl group. Alkyl groups can have one ormore chiral centers. Alkyl groups can be independently substituted byhalogen atoms, hydroxyl groups, cycloalkyl groups, amino groups,heterocyclic groups, aryl groups, carboxylic acid groups, phosphonicacid groups, sulphonic acid groups, phosphoric acid groups, nitrogroups, amide groups, sulfonamide groups, ester groups, ketone groups.

The term “cycloalkyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms derived from a saturated cyclichydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic.Cycloalkyl can be independently substituted by halogen atoms, sulfonylC₁₋₈ alkyl groups, sulfoxide C₁₋₈ alkyl groups, sulfonamide groups,nitro groups, cyano groups, —OC₁₋₈ alkyl groups, —SC₁₋₈ alkyl groups,—C₁₋₈ alkyl groups, —C₂₋₆ alkenyl groups, —C₂₋₆ alkynyl groups, ketonegroups, alkylamino groups, amino groups, aryl groups, C₃₋₈ cycloalkylgroups or hydroxyl groups.

The term “cycloalkenyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms derived from a saturatedcycloalkyl having at least one double bond.

Cycloalkenyl groups can be monocyclic or polycyclic. Cycloalkenyl groupscan be independently substituted by halogen atoms, sulfonyl groups,sulfoxide groups, nitro groups, cyano groups, —OC₁₋₆ alkyl groups,—SC₁₋₆ alkyl groups, —C₁₋₆ alkyl groups, —C₂₋₆ alkenyl groups, —C₂₋₆alkynyl groups, ketone groups, alkylamino groups, amino groups, arylgroups, C₃₋₈ cycloalkyl groups or hydroxyl groups.

The term “halogen”, as used herein, refers to an atom of chlorine,bromine, fluorine, iodine.

The term “alkenyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one double bond. One methylene (—CH₂—) group, ofthe alkenyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen,carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, bya divalent C₃₋₈ cycloalkyl, by a divalent heterocycle, or by a divalentaryl group. C₂₋₆ alkenyl can be in the E or Z configuration. Alkenylgroups can be substituted by alkyl groups, as defined above or byhalogen atoms.

The term “alkynyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one triple bond. One methylene (—CH₂—) group, ofthe alkynyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen,carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, bya divalent C₃₋₈ cycloalkyl, by a divalent heterocycle, or by a divalentaryl group. Alkynyl groups can be substituted by alkyl groups, asdefined above, or by halogen atoms.

The term “heterocycle” as used herein, refers to a 3 to 10 memberedring, which can be aromatic or non-aromatic, saturated or unsaturated,containing at least one heteroatom selected form oxygen, nitrogen,sulfur, or combinations of at least two thereof, interrupting thecarbocyclic ring structure. The heterocyclic ring can be interrupted bya C═O; the S and N heteroatoms can be oxidized. Heterocycles can bemonocyclic or polycyclic. Heterocyclic ring moieties can be substitutedby halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyanogroups, —OC₁₋₆ alkyl groups, —SC₁₋₆ alkyl groups, —C₁₋₈ alkyl groups,—C₂₋₆ alkenyl groups, —C₂₋₆ alkynyl groups, ketone groups, alkylaminogroups, amino groups, aryl groups, C₃₋₈ cycloalkyl groups or hydroxylgroups.

The term “aryl” as used herein, refers to an organic moiety derived froman aromatic hydrocarbon consisting of a ring containing 6 to 10 carbonatoms, by removal of one hydrogen atom. Aryl can be substituted byhalogen atoms, sulfonyl C₁₋₆ alkyl groups, sulfoxide C₁₋₆ alkyl groups,sulfonamide groups, carboxcyclic acid groups, C₁₋₆ alkyl carboxylates(ester) groups, amide groups, nitro groups, cyano groups, —OC₁₋₆ alkylgroups, —SC₁₋₆ alkyl groups, —C₁₋₆ alkyl groups, —C₂₋₆ alkenyl groups,—C₂₋₆ alkynyl groups, ketone groups, aldehydes, alkylamino groups, aminogroups, aryl groups, C₃₋₈ cycloalkyl groups or hydroxyl groups. Arylscan be monocyclic or polycyclic.

The term “hydroxyl” as used herein, represents a group of formula “—OH”.

The term “carbonyl” as used herein, represents a group of formula“—C(O)—”.

The term “ketone” as used herein, represents an organic compound havinga carbonyl group linked to a carbon atom such as —C(O)R^(x) whereinR^(x) can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle asdefined above.

The term “ester” as used herein, represents an organic compound having acarbonyl group linked to a carbon atom such as —C(O)OR^(x) wherein R^(x)can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as definedabove.

The term “amine” as used herein, represents a group of formula“—NR^(x)R^(y)”, wherein R^(x) and R^(y) can be the same or independentlyH, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

The term “carboxyl” as used herein, represents a group of formula“—C(O)O—”.

The term “sulfonyl” as used herein, represents a group of formula “—SO₂⁻”.

The term “sulfate” as used herein, represents a group of formula“—O—S(O)₂—O—”.

The term “sulfonate” as used herein, represents a group of the formula“—S(O)₂—O—”.

The term “carboxylic acid” as used herein, represents a group of formula“—C(O)OH”.

The term “nitro” as used herein, represents a group of formula “—NO₂”.

The term “cyano” as used herein, represents a group of formula “—CN”.

The term “amide” as used herein, represents a group of formula“—C(O)NR^(x)R^(y),” wherein R^(x) and R^(y) can be the same orindependently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle asdefined above.

The term “sulfonamide” as used herein, represents a group of formula“—S(O)₂NR^(x)R^(y)” wherein R^(x) and R^(y) can be the same orindependently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle asdefined above.

The term “sulfoxide” as used herein, represents a group of formula“—S(O)—”.

The term “phosphonic acid” as used herein, represents a group of formula“—P(O)(OH)₂”.

The term “phosphoric acid” as used herein, represents a group of formula“—OP(O)(OH)₂”.

The term “sulphonic acid” as used herein, represents a group of formula“—S(O)₂OH”.

The formula “H”, as used herein, represents a hydrogen atom.

The formula “O”, as used herein, represents an oxygen atom.

The formula “N”, as used herein, represents a nitrogen atom.

The formula “S”, as used herein, represents a sulfur atom.

Other defined terms are used throughout this specification:

“Ac” refers to acetyl

“DCE” refers to dichloroethane

“DCM” refers to dichloromethane

“DMAP” refers to dimethylaminopyridine

“EDCI” refers to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide “Et”refers to ethyl

“iPr” refers to i-propyl

“Me” refers to methyl

“MeOH” refers to methanol

“PDGF” refers to platelet derived growth factor

“Ph” refers to phenyl

“PKs” refers to protein kinase

“RTKs” refers to receptor tyrosine kinase

“rt” refers to room temperature

“tBu” refers to t-butyl.

“THF” refers to tetrahydrofuran

“VEGF” refers to vascular endothelial growth factor

“VEGFR” refers to vascular endothelial growth factor receptor

Compounds of the invention are tabulated in Table 1:

TABLE 1 List of compound names and structures Example Structure CompoundName 1

6-amino-N-[dimethyl(oxido)- λ⁴-sulfanylidene]-5-[5-({[(3-methylphenyl)amino]carbonyl} amino)-1-benzothien-2- yl]nicotinamide 2

6-amino-5-[5-({[(3-chloro-4- fluorophenyl)amino]carbonyl}amino)-1-benzothien-2-yl]-N- [dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamide 3

6-amino-N-[dimethyl(oxido)- λ⁴-sulfanylidene]-5-[5-({[(2- fluoro-5-methylphenyl)amino]carbonyl} amino)-1-benzothien-2- yl]nicotinamide 4

6-amino-5-{5- [(anilinocarbonyl)amino]-1- benzothien-2-yl}-N-[dimethyl(oxido)-λ⁴- sulfanylidene]nicotinamide 5

6-amino-5-{5-[({[4-chloro-3- (trifluoromethyl)phenyl]amino}carbonyl)amino]-1- benzothien-2-yl}-N- [dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamide 6

6-amino-N-[dimethyl(oxido)- λ⁴-sulfanylidene]-5-{5-[({[2- fluoro-5-(trifluoromethyl)phenyl]amino} carbonyl)amino]-1-benzothien-2-yl}nicotinamide 7

methyl 6-amino-5-{5-[({[3- (trifluoromethyl)phenyl]amino}carbonyl)amino]-1- benzothien-2-yl}nicotinate 8

methyl 6-amino-5-{5-[({[2- fluoro-5- (trifluoromethyl)phenyl]amino}carbonyl)amino]-1- benzothien-2-yl}nicotinate 9

methyl 6-amino-5-{5-[({[4- chloro-3- (trifluoromethyl)phenyl]amino}carbonyl)amino]-1- benzothien-2-yl}nicotinate 10

methyl 6-amino-5-[5-({[(2- fluoro-5- methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinate 11

methyl 6-amino-5-[5-({[(3- methylphenyl)amino]carbonyl}amino)-1-benzothien-2- yl]nicotinate 12

methyl 6-amino-5-[5-({[(3- chloro-4- fluorophenyl)amino]carbonyl}amino)-1-benzothien-2- yl]nicotinate 13

methyl 6-amino-5-[5-({[(4- methylphenyl)amino]carbonyl}amino)-1-benzothien-2- yl]nicotinate 14

methyl 6-amino-5-[5-({[(2- fluorophenyl)amino]carbonyl}amino)-1-benzothien-2- yl]nicotinate 15

methyl 6-amino-5-{5- [(anilinocarbonyl)amino]-1-benzothien-2-yl}nicotinate 16

methyl 6-amino-5-[5-({[(2,4- difluorophenyl)amino]carbonyl}amino)-1-benzothien-2- yl]nicotinate 17

6-amino-5-[5-({[(3-chloro-4- fluorophenyl)amino]carbonyl}amino)-1-benzothien-2- yl]nicotinic acid 18

6-amino-5-[5-({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)-1-benzothien-2- yl]nicotinic acid 19

6-amino-5-[5-({[(3- methylphenyl)amino]carbonyl} amino)-1-benzothien-2-yl]nicotinic acid 20

6-amino-5-[5-({[(3- methylphenyl)amino]carbonyl} amino)-1-benzothien-2-yl]nicotinamide 21

methyl 4-[({6-amino-5-[5-({[(3- methylphenyl)amino]carbonyl}amino)-1-benzothien-2- yl]pyridin-3- yl}carbonyl)amino]butanoate 22

methyl 6-[({6-amino-5-[5-({[(3- methylphenyl)amino]carbonyl}amino)-1-benzothien-2- yl]pyridin-3- yl}carbonyl)amino]hexanoate 23

1-{2-[2-amino-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3- yl]-1-benzothien-5-yl}-3-[2- fluoro-5-(trifluoromethyl)phenyl]urea 24

1-{2-[2-amino-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3- yl]-1-benzothien-5-yl}-3-[3-(trifluoromethyl)phenyl]urea 25

1-{2-[2-amino-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3- yl]-1-benzothien-5-yl}-3-[4- chloro-3-(trifluoromethyl)phenyl]ure 26

1-{2-[2-amino-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3- yl]-1-benzothien-5-yl}-3-(2-fluoro-5-methylphenyl)urea 27

1-{2-[2-amino-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3- yl]-1-benzothien-5-yl}-3-(3-chloro-4-fluorophenyl)urea 28

1-{2-[2-amino-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3- yl]-1-benzothien-5-yl}-3-(3-ethylphenyl)urea 29

1-{2-[2-amino-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3- yl]-1-benzothien-5-yl}-3-(3-methylphenyl)urea 30

1-{2-[2-amino-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3- yl]-1-benzothien-5-yl}-3- phenylurea 31

{6-amino-5-[5-({[(3- methylphenyl)amino]carbonyl} amino)-1-benzothien-2-yl]pyridin-3-yl}boronic acid 32

(6-amino-5-{5- [(anilinocarbonyl)amino]-1- benzothien-2-yl}pyridin-3-yl)boronic acid 33

6-amino-N-[dimethyl(oxido)- λ⁴-sulfanylidene]-5-{5-[(3-methyl-2-furoyl)amino]-1- benzothien-2-yl}nicotinamide 34

6-amino-5-(5-{[4-chloro-3- (trifluoromethyl)benzoyl]amino}1-benzothien-2-yl)-N- [dimethyl(oxido)-λ⁴- sulfanylidene]nicotinamide 35

6-amino-N-[dimethyl(oxido)- λ⁴-sulfanylidene]-5-{5-[(2- fluoro-5-methylbenzoyl)amino]-1- benzothien-2-yl}nicotinamide 36

6-amino-5-[5-(benzoylamino)- 1-benzothien-2-yl]-N- [dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamide 37

6-amino-N-[dimethyl(oxido)- λ⁴-sulfanylidene]-5-{5-[(3-methylbenzoyl)amino]-1- benzothien-2-yl}nicotinamide 38

6-amino-N-[dimethyl(oxido)- λ⁴-sulfanylidene]-5-(5-{[2- fluoro-5-(trifluoromethyl)benzoyl]amino- 1-benzothien-2- yl)nicotinamide 39

methyl 6-amino-5-{5-[(3- methyl-2-furoyl)amino]-1-benzothien-2-yl}nicotinate 40

methyl 6-amino-5-{5-[(3- methylbenzoyl)amino]-1-benzothien-2-yl}nicotinate 41

methyl 6-amino-5-{5-[(2- fluoro-5- methylbenzoyl)amino]-1-benzothien-2-yl}nicotinate 42

6-amino-5-[5-[5 (benzoylamino)-1-benzothien- 2-yl]nicotinate 43

methyl 6-amino-5-{5-[(3- chloro-4- fluorobenzoyl)amino]-1-benzothien-2-yl}nicotinate 44

methyl 6-amino-5-(5-{[2- fluoro-5- (trifluoromethyl)benzoyl]amino-1-benzothien-2-yl)nicotinate 45

methyl 6-amino-5-{5-[(1- benzofuran-2- ylcarbonyl)amino]-1-benzothien-2-yl}nicotinate 46

N-[2-(2-aminopyridin-3-yl)-1- benzothien-5-yl]-3- methylbenzamide 47

N-[2-(2-aminopyridin-3-yl)-1- benzothien-5-yl]benzamide 48

2-(2-aminopyridin-3-yl)-N-(3- methylphenyl)-1- benzothiophene-5-carboxamide 49

2-(2-aminopyridin-3-yl)-N-(5- tert-butylisoxazol-3-yl)-1-benzothiophene-5- carboxamide 50

2-(2-aminopyridin-3-yl)-N-(3- methylbenzyl)-1- benzothiophene-5-carboxamide 51

2-(2-aminopyridin-3-yl)-N-(2- fluoro-5-methylphenyl)-1-benzothiophene-5- carboxamide 52

2-(2-aminopyridin-3-yl)-N-(3- chloro-4-fluorophenyl)-1-benzothiophene-5- carboxamide 53

methyl 5-[N-({6-amino-5-[5- ({[(3- methylphenyl)amino]carbonyl}amino)-1-benzothien-2- yl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate 54

methyl 5-[N-({6-amino-5-[5- ({[(2-fluoro-5- methylphenyl)amino]carbonyl}amino)-1-benzothien-2- yl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate 55

methyl 5-[N-({6-amino-5-[5- ({[(3-chloro-4- fluorophenyl)amino]carbonyl}amino)-1-benzothien-2- yl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate 56

6-amino-N-[bis(3- hydroxypropyl)(oxido)-λ⁴- sulfanylidene]-5-[5-({[(3-methylphenyl)amino]carbonyl} amino)-1-benzothien-2- yl]nicotinamide 57

N-[dimethyl(oxido)-λ⁴- sulfanylidene]-5-{5-[({[2- fluoro-5-(trifluoromethyl)phenyl]amino} carbonyl)amino]-1-benzothien-2-yl}nicotinamide 58

5-{5-[({[4-chloro-3- (trifluoromethyl)phenyl]amino} carbonyl)amino]-1-benzothien-2-yl}-N- [dimethyl(oxido)-λ⁴- sulfanylidene]nicotinamide 59

6-amino-N-[dimethyl(oxido)- λ⁴-sulfanylidene]-5-[4-({[(2-fluoro-5-methylphenyl) amino]carbonyl}amino)phenyl] nicotinamide 60

6-amino-N-[dimethyl(oxido)- λ⁴-sulfanylidene]-5-[4-({[(2- fluoro-5-methylphenyl)amino]carbonyl} amino)phenyl]nicotinamide 61

[6-amino-5-(4-{[(2-fluoro-5- methylphenyl)carbamoyl]amino}phenyl)pyridin-3-yl]boronic acid 62

1-{4-[2-amino-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3- yl]phenyl}-3-(2-fluoro-5- methylphenyl)urea63

1-{4-[2-amino-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3- yl]phenyl}-3-phenylurea 64

dimethyl {6-amino-5-[4-({[3- (trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyridin-3- yl}phosphonate 65

diethyl [6-amino-5-(4-{[(2- fluoro-5- methylphenyl)carbamoyl]amino}phenyl)pyridin-3- yl]phosphonate 66

dimethyl {6-amino-5-[4-({[2- fluoro-5-(trifluoromethyl)phenyl]carbamoyl} amino)phenyl]pyridin-3-yl}phosphonate 67

dimethyl [6-amino-5-(4-{[(2- fluoro-5- methylphenyl)carbamoyl]amino}phenyl)pyridin-3- yl]phosphonate 68

dimethyl (6-amino-5-{4- [(phenylcarbamoyl)amino]phenyl}pyridin-3-yl)phosphonate 69

6-amino-N-[bis(3- hydroxypropyl)(oxido)-λ⁶- sulfanylidene]-5-(4-{[(3-methylphenyl)carbamoyl]amino} phenyl)pyridine-3- carboxamide 70

dimethyl 5,5'-(N-{[6-amino-5- (4-{[(3- methylphenyl)carbamoyl]amino}phenyl)pyridin-3- yl]carbonyl}sulfonimidoyl) dipentanoate 71

dimethyl 5,5'-(N-{[6-amino-5- (4-{[(2-fluoro-5-methylphenyl)carbamoyl]amino} phenyl)pyridin-3-yl]carbonyl}sulfonimidoyl) dipentanoate 72

dimethyl 5,5′[N-({6-amino-5- [4-({[3- (trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyridin-3- yl}carbonyl)sulfonimidoyl] dipentanoate 73

methyl 6-amino-5-(4-{[(2- fluoro-5- methylphenyl)carbamoyl]amino}phenyl)pyridine-3- carboxylate 74

methyl 6-amino-5-[4-({[2- fluoro-5- (trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyridine- 3-carboxylate 75

methyl 6-amino-5-[4-({[4- chloro-3- (trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyridine- 3-carboxylate 76

methyl 6-amino-5-{4- [(phenylcarbamoyl)amino]phenyl}pyridine-3-carboxylate

Compounds of formula I and of formula II are useful as protein kinaseinhibitors. As such, compounds of formula I and of formula II will beuseful for treating diseases related to unregulated protein kinasesignal transduction, for example, cancer, blood vessel proliferativedisorders, fibrotic disorders, inflammatory disorders andneurodegenerative diseases. In particular, the compounds of the presentinvention are useful for treatment of mesangial cell proliferativedisorders and metabolic diseases, lung carcinomas, breast carcinomas,Non Hodgkin's lymphomas, ovarian carcinoma, pancreatic cancer, malignantpleural mesothelioma, melanoma, arthritis, restenosis, hepaticcirrhosis, atherosclerosis, psoriasis, rosacea, diabetic mellitus, woundhealing, inflammation and neurodegenerative diseases and preferablyophthalmic diseases, i.e. diabetic retinopathy, retinopathy ofprematurity, macular edema, retinal vein occlusion, exudative orneovascular age-related macular degeneration, high-risk eyes (i.e.fellow eyes have neovascular age-related macular degeneration) with dryage-related macular degeneration, neovascular disease associated withretinal vein occlusion, neovascular disease (including choroidalneovascularization) associated with the following: pathologic myopia,pseudoxanthoma elasticum, optic nerve drusen, traumatic choroidalrupture, atrophic macular degeneration, geographic atrophy, centralserous retinopathy, cystoid macular edema, diabetic retinopathy,proliferative diabetic retinopathy, diabetic macular edema, rubeosisiridis, retinopathy of prematurity, Central and branch retinal veinocclusions, inflammatory/infectious retinal, neovascularization/edema,corneal neovascularization, hyperemia related to an actively inflamedpterygia, recurrent pterygia following excisional surgery,post-excision, progressive pterygia approaching the visual axis,prophylactic therapy to prevent recurrent pterygia, of post-excision,progressive pterygia approaching the visual axis, chronic low gradehyperemia associated with pterygia, neovascular glaucoma, irisneovascularization, idiopathic etiologies, presumed ocularhistoplasmosis syndrome, retinopathy of prematurity, chronic allergicconjunctivitis, ocular rosacea, blepharoconjunctivitis, recurrentepiscleritis, keratoconjunctivitis sicca, ocular graft vs host disease,etc.

Some compounds of Formula I and of Formula II and some of theirintermediates may have at least one asymmetric center in theirstructure. This asymmetric center may be present in an R or Sconfiguration, said R and S notation is used in correspondence with therules described in Pure Appli. Chem. (1976), 45, 11-13.

The term “pharmaceutically acceptable salts” refers to salts orcomplexes that retain the desired biological activity of the aboveidentified compounds and exhibit minimal or no undesired toxicologicaleffects. The “pharmaceutically acceptable salts” according to theinvention include therapeutically active, non-toxic base or acid saltforms, which the compounds of Formula I and of Formula II are able toform.

The acid addition salt form of a compound of Formula I and of Formula IIthat occurs in its free form as a base can be obtained by treating thefree base with an appropriate acid such as an inorganic acid, forexample, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoricacid, nitric acid and the like; or an organic acid such as for example,acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvicacid, malonic acid, fumaric acid, maleic acid, oxalic acid, tartaricacid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannicacid, pamoic acid, citric acid, methylsulfonic acid, ethanesulfonicacid, benzenesulfonic acid, formic and the like (Handbook ofPharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds),Verlag Helvetica Chimica Acta-Zürich, 2002, 329-345).

The base addition salt form of a compound of Formula I and of Formula IIthat occurs in its acid form can be obtained by treating the acid withan appropriate base such as an inorganic base, for example, sodiumhydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide,ammonia and the like; or an organic base such as for example,L-Arginine, ethanolamine, betaine, benzathine, morpholine and the like.(Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G.Wermuth (Eds), Verlag Helvetica Chimica Acta-Zürich, 2002, 329-345).

Compounds of Formula I and of Formula II and their salts can be in theform of a solvate, which is included within the scope of the presentinvention. Such solvates include for example hydrates, alcoholates andthe like.

With respect to the present invention reference to a compound orcompounds, is intended to encompass that compound in each of itspossible isomeric forms and mixtures thereof unless the particularisomeric form is referred to specifically.

Compounds according to the present invention may exist in differentpolymorphic forms. Although not explicitly indicated in the aboveformula, such forms are intended to be included within the scope of thepresent invention.

The actual amount of the compound to be administered in any given casewill be determined by a physician taking into account the relevantcircumstances, such as the severity of the condition, the age and weightof the patient, the patient's general physical condition, the cause ofthe condition, and the route of administration.

The patient will be administered the compound orally in any acceptableform, such as a tablet, liquid, capsule, powder and the like, or otherroutes may be desirable or necessary, particularly if the patientsuffers from nausea. Such other routes may include, without exception,transdermal, parenteral, subcutaneous, intranasal, via an implant stent,intrathecal, intravitreal, topical to the eye, back to the eye,intramuscular, intravenous, and intrarectal modes of delivery.Additionally, the formulations may be designed to delay release of theactive compound over a given period of time, or to carefully control theamount of drug released at a given time during the course of therapy.

In another embodiment of the invention, there are providedpharmaceutical compositions including at least one compound of theinvention in a pharmaceutically acceptable carrier thereof. The phrase“pharmaceutically acceptable” means the carrier, diluent or excipientmust be compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a patch, amicelle, a liposome, and the like, wherein the resulting compositioncontains one or more compounds of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. Inventioncompounds may be combined, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, and any other formsuitable for use. The carriers which can be used include glucose,lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Inventioncompounds are included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or diseasecondition.

Pharmaceutical compositions containing invention compounds may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known in the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting of asweetening agent such as sucrose, lactose, or saccharin, flavoringagents such as peppermint, oil of wintergreen or cherry, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets containing invention compounds inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be, forexample, (1) inert diluents such as calcium carbonate, lactose, calciumphosphate or sodium phosphate; (2) granulating and disintegrating agentssuch as corn starch, potato starch or alginic acid; (3) binding agentssuch as gum tragacanth, corn starch, gelatin or acacia, and (4)lubricating agents such as magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the invention compounds are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They may also be in the form of soft gelatin capsules whereinthe invention compounds are mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

Pharmaceutical compositions containing invention compounds may be in aform suitable for topical use, for example, as oily suspensions, assolutions or suspensions in aqueous liquids or nonaqueous liquids, or asoil-in-water or water-in-oil liquid emulsions. Pharmaceuticalcompositions may be prepared by combining a therapeutically effectiveamount of at least one compound according to the present invention, or apharmaceutically acceptable salt thereof, as an active ingredient withconventional ophthalmically acceptable pharmaceutical excipients and bypreparation of unit dosage suitable for topical ocular use. Thetherapeutically efficient amount typically is between about 0.0001 andabout 5% (w/v), preferably about 0.001 to about 2.0% (w/v) in liquidformulations.

For ophthalmic application, preferably solutions are prepared using aphysiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 4.5 and 8.0with an appropriate buffer system, a neutral pH being preferred but notessential. The formulations may also contain conventionalpharmaceutically acceptable preservatives, stabilizers and surfactants.Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate. A preferred surfactant is, for example,Tween 80. Likewise, various preferred vehicles may be used in theophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose cyclodextrin and purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar manner an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. The preferred chelating agent isedentate disodium, although other chelating agents may also be used inplace of or in conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative  0-0.10 vehicle 0-40 tonicity adjustor 0-10 buffer 0.01-10   pHadjustor q.s. pH 4.5-7.8 antioxidant as needed surfactant as neededpurified water to make 100%

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The ophthalmic formulations of the present invention are convenientlypackaged in forms suitable for metered application, such as incontainers equipped with a dropper, to facilitate application to theeye. Containers suitable for dropwise application are usually made ofsuitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution. One package may contain oneor more unit doses. Especially preservative-free solutions are oftenformulated in non-resealable containers containing up to about ten,preferably up to about five units doses, where a typical unit dose isfrom one to about 8 drops, preferably one to about 3 drops. The volumeof one drop usually is about 20-35 μl.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

The compounds of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention compounds with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner. The present invention isfurther directed to pharmaceutical compositions comprising apharmaceutically effective amount of one or more of the above-describedcompounds and a pharmaceutically acceptable carrier or excipient,wherein said compositions are effective for treating the above diseasesand conditions; especially ophthalmic diseases and conditions. Such acomposition is believed to modulate signal transduction by a proteinkinase, either by inhibition of catalytic activity, affinity to ATP orability to interact with a substrate.

More particularly, the compositions of the present invention may beincluded in methods for treating diseases comprising proliferation,fibrotic or metabolic disorders, for example cancer, fibrosis,psoriasis, rosacea, atherosclerosis, arthritis, and other disordersrelated to abnormal vasculogenesis and/or angiogenesis, such asexudative age related macular degeneration and diabetic retinopathy.

The present invention is further directed to pharmaceutical compositionscomprising a pharmaceutically effective amount of the above-describedcompounds and a pharmaceutically acceptable carrier or excipient. Such acomposition is believed to modulate signal transduction by a proteinkinase, tyrosine kinase, or serine threonine kinase either by inhibitionof catalytic activity, affinity to ATP or ability to interact with asubstrate.

The present invention relates to compounds capable of regulating and/ormodulating protein kinase signal transduction and more particularlyreceptor and non-receptor protein kinase signal transduction.

Receptor tyrosine kinase mediated signal transduction is initiated byextracellular interaction with a specific growth factor (ligand),followed by receptor dimerization, transient stimulation of theintrinsic protein tyrosine kinase activity and phosphorylation. Bindingsites are thereby created for intracellular signal transductionmolecules and lead to the formation of complexes with a spectrum ofcytoplasmic signaling molecules that facilitate the appropriate cellularresponse (e.g., cell division, metabolic effects and responses to theextracellular microenvironment).

It has been shown that tyrosine phosphorylation sites in growth factorreceptors function as high-affinity binding sites for SH2 (src homology)domains of signaling molecules. Several intracellular substrate proteinsthat associate with receptor tyrosine kinases have been identified. Theymay be divided into two principal groups: (1) substrates which have acatalytic domain; and (2) substrates which lack such domain but serve asadapters and associate with catalytically active molecules. Thespecificity of the interactions between receptors and SH2 domains oftheir substrates is determined by the amino acid residues immediatelysurrounding the phosphorylated tyrosine residue. Differences in thebinding affinities between SH2 domains and the amino acid sequencessurrounding the phosphotyrosine residues on particular receptors areconsistent with the observed differences in their substratephosphorylation profiles. These observations suggest that the functionof each receptor tyrosine kinase is determined not only by its patternof expression and ligand availability but also by the array ofdownstream signal transduction pathways that are activated by aparticular receptor. Thus, phosphorylation provides an importantregulatory step which determines the selectivity of signaling pathwaysrecruited by specific growth factor receptors, as well asdifferentiation factor receptors.

Protein kinase signal transduction results in, among other responses,cell proliferation, differentiation and metabolism. Abnormal cellproliferation may result in a wide array of disorders and diseases,including the development of neoplasia such as carcinoma, sarcoma,leukemia, glioblastoma, hemangioma, psoriasis, arteriosclerosis,arthritis and diabetic retinopathy (or other disorders related touncontrolled angiogenesis and/or vasculogenesis, e.g. maculardegeneration).

This invention is therefore directed to compounds which regulate,modulate and/or inhibit protein kinase signal transduction by affectingthe enzymatic activity of the PKs and interfering with the signaltransduced by such proteins. More particularly, the present invention isdirected to compounds which regulate, modulate and/or inhibit theproteinkinase mediated signal transduction pathways as a therapeuticapproach to cure many kinds of solid tumors, including but not limitedto carcinoma, sarcoma, leukemia, erythroblastoma, glioblastoma,meningioma, astrocytoma, melanoma and myoblastoma. Indications mayinclude, but are not limited to brain cancers, bladder cancers, ovariancancers, gastric cancers, pancreas cancers, colon cancers, bloodcancers, lung cancers and bone cancers.

The present invention concerns also processes for preparing thecompounds of Formula I and of Formula II. The compounds of formula I andof formula II according to the invention can be prepared analogously toconventional methods as understood by the person skilled in the art ofsynthetic organic chemistry. The following Synthetic Schemes set forthbelow, illustrate how the compounds according to the invention can bemade.

At this stage, those skilled in the art will appreciate that manyadditional compounds that fall under the scope of the invention may beprepared by performing various common chemical reactions. Details ofcertain specific chemical transformations are provided in the examples.

Those skilled in the art will be able to routinely modify and/or adaptthe following scheme to synthesize any compounds of the inventioncovered by Formula I and of Formula II.

The present invention is not to be limited in scope by the exemplifiedembodiments which are intended as illustrations of single aspects of theinvention only. Indeed, various modifications of the invention inaddition to those described herein will become apparent to those skilledin the art from the foregoing description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method of regulating, modulating orinhibiting proteinkinases, whether of the receptor or non-receptorclass, for the prevention and/or treatment of disorders related tounregulated protein kinase signal transduction, including cell growth,metabolic, and blood vessel proliferative disorders, which comprisesadministering a pharmaceutical composition comprising a therapeuticallyeffective amount of at least one kinase inhibitor as described herein.

In another aspect, the invention provides the use of at least one kinaseinhibitor for the manufacture of a medicament for the treatment of adisease or a condition mediated by tyrosine kinases in a mammal.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise.

It will be readily apparent to those skilled in the art that some of thecompounds of the invention may contain one or more asymmetric centers,such that the compounds may exist in enantiomeric as well as indiastereomeric forms. Unless it is specifically noted otherwise, thescope of the present invention includes all enantiomers, diastereomersand racemic mixtures. Some of the compounds of the invention may formsalts with pharmaceutically acceptable acids or bases, and suchpharmaceutically acceptable salts of the compounds described herein arealso within the scope of the invention.

The present invention includes all pharmaceutically acceptableisotopically enriched compounds. Any compound of the invention maycontain one or more isotopic atoms enriched or different than thenatural ratio such as deuterium ²H (or D) in place of hydrogen ¹H (or H)or use of ¹³C enriched material in place of ¹²C and the like. Similarsubstitutions can be employed for N, O and S. The use of isotopes mayassist in analytical as well as therapeutic aspects of the invention.For example, use of deuterium may increase the in vivo half-life byaltering the metabolism (rate) of the compounds of the invention. Thesecompounds can be prepared in accord with the preparations described byuse of isotopically enriched reagents.

The following examples are for illustrative purposes only and are notintended, nor should they be construed as limiting the invention in anymanner. Those skilled in the art will appreciate that variations andmodifications of the following examples can be made without exceedingthe spirit or scope of the invention.

As will be evident to those skilled in the art, individual isomericforms can be obtained by separation of mixtures thereof in conventionalmanner. For example, in the case of diasteroisomeric isomers,chromatographic separation may be employed.

Compound names were generated with ACDLabs version 12.5. Some of theintermediate and reagent names used in the examples were generated withsoftware such as Chem Bio Draw Ultra version 12.0 or Auto Nom 2000 fromMDL ISIS Draw 2.5 SP1.

In general, characterization of the compounds is performed according tothe following methods; NMR spectra are recorded on 300 or 600 MHz Varianand acquired at room temperature. Chemical shifts are given in ppmreferenced either to internal TMS or to the solvent signal.

All the reagents, solvents, catalysts for which the synthesis is notdescribed are purchased from chemical vendors such as Sigma Aldrich,Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, TransWorld Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth,Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex,MIC-scientific, Ltd; however some known intermediates, were preparedaccording to published procedures.

Usually the compounds of the invention were purified by medium pressureliquid chromatography, unless noted otherwise.

Preparation 1

tert-butyl{2-[2-amino-5-({[dimethyl(oxido)-λ⁴-sulfanylidene]amino}carbonyl)pyridin-3-yl]-1-benzothien-5-yl}carbamate

To the degassed mixture of6-amino-N-[dimethyl(oxido)-λ⁴-sulfanylidene]-5-iodonicotinamide (1.19 g,3.51 mmol, 1 eq), 5-tert-butoxycarbonylaminobenzothiophene-2-boronicacid (1.52 g, 1.15 eq), and aq sodium carbonate (2M, 5.27 mL, 3 eq) indioxane (7.5 mL) was added Ph₃P (184 mg, 0.2 eq) and Pd(OAc)₂ (79 mg,0.1 eq). The mixture was heated to 50° C. with vigorous stirring for 30minutes. The reaction mixture was then partitioned between aq NH₄Cl andEtOAc. The organic layer was isolated, washed with sat aq NaHCO₃, brine,and finally dried with anhydrous sodium sulfate. The upper solution wasdecanted, concentrated, and the foamy oily residue was subject to agradient column chromatography (EtOAc-Hex 3:1 to 6:1) yieldingtert-butyl{2-[2-amino-5-({[dimethyl(oxido)-λ⁴-sulfanylidene]amino}carbonyl)pyridin-3-yl]-1-benzothien-5-yl}carbamateas a white solid in amount of 1.274 g (79%).

Preparation 2

6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamide

To the mixture of tert-butyl{2-[2-amino-5-({[dimethyl(oxido)-λ⁴-sulfanylidene]amino}carbonyl)pyridin-3-yl]-1-benzothien-5-yl}carbamate(1.23 g, 2.67 mmol, 1 eq) in dichloromethane (6 mL) at 0° C. was addeddropwise trifluoroacetic acid (5.16 mL, 20 eq). During this process thereaction mixture became a brown solution. The reaction was stirred at 0°C. for 15 minutes and then at room temperature for 3 hours. The reactionwas partitioned between DCM and cold saturated aq NaHCO₃. The organiclayer was isolated, washed with brine and dried with anhydrous sodiumsulfate. The clear layer was decanted, concentrated, and the brown solidresidue was treated with EtOAc. An orange colored solid was obtainedupon filtration giving6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamidein amount of 0.837 g (87%).

Example 1

6-amino-N-[dimethyl(oxido)-λ⁴-sulfanylidene]-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinamide

To the solution of6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamide(72 mg, 0.2 mmol. 1 eq) in anhydrous DMF (2 mL) at room temperature wasadded dropwise m-tolylisocyanate (0.03 mL, 1.2 eq). After the reactionsolution was stirred at rt for 2 hours, it was diluted with EtOAc,washed sequentially with saturated aq NaHCO₃, aq NH₄Cl, brine, andfinally dried with anhydrous sodium sulfate. The organic layer wasdecanted, concentrated, and the solid residue was triturated with DCMwith stirring. A lightly pink solid was obtained upon filtration toyield6-amino-N-[dimethyl(oxido)-λ⁴-sulfanylidene]-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinamidein amount of 91 mg (92%).

¹H NMR (DMSO-d₆) δ: 8.78 (s, 1H), 8.61 (s, 1H), 8.61 (d, J=2.1 Hz, 1H),8.10 (dd, J=2.1, 0.3 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H), 7.87 (d, J=8.5 Hz,1H), 7.59 (s, 1H), 7.37 (dd, J=8.8, 2.1 Hz, 1H), 7.32 (s, 1H), 7.25 (d,J=8.2 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 6.80 (d, J=7.3 Hz, 1H), 6.76 (s,2H), 3.44 (s, 6H), 2.29 (s, 3H).

Example 2

6-amino-5-[5-({[(3-chloro-4-fluorophenyl)amino]carbonyl}amino)-1-benzothien-2-yl]-N-[dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamide

In a manner similar to that described in Example 1,6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamideand 2-chloro-1-fluoro-4-isocyanatobenzene were converted to the titlecompound.

¹H NMR (DMSO-d₆) δ: 8.91 (d, J=4.7 Hz, 2H), 8.61 (d, J=2.3 Hz, 1H), 8.08(d, J=2.1 Hz, 1H), 8.02 (d, J=2.3 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.83(dd, J=6.7, 2.1 Hz, 1H), 7.59 (s, 1H), 7.38 (dd, J=8.8, 2.1 Hz, 1H),7.32-7.35 (m, 2H), 6.75 (s, 2H), 3.44 (s, 6H).

Example 3

6-amino-N-[dimethyl(oxido)-λ⁴-sulfanylidene]-5-[5-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinamide

In a manner similar to that described in Example 1,6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamideand 1-fluoro-2-isocyanato-4-methylbenzene were converted to the titlecompound.

¹H NMR (DMSO-d₆) δ: 9.18 (s, 1H), 8.61 (d, J=2.1 Hz, 1H), 8.50 (d, J=2.6Hz, 1H), 8.12 (d, J=2.1 Hz, 1H), 8.01-8.04 (m, 2H), 7.89 (d, J=8.8 Hz,1H), 7.60 (s, 1H), 7.35 (dd, J=8.5, 2.1 Hz, 1H), 7.11 (dd, J=11.3, 8.4Hz, 1H), 6.79-6.82 (m, 1H), 6.75 (s, 2H), 3.44 (s, 6H), 2.28 (s, 3H).

Example 4

6-amino-5-{5-[(anilinocarbonyl)amino]-1-benzothien-2-yl}-N-[dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamide

In a manner similar to that described in Example 1,6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamideand isocyanatobenzene were converted to the title compound.

¹H NMR (DMSO-d₆) δ: 8.80 (s, 1H), 8.69 (s, 1H), 8.60 (d, J=2.3 Hz, 1H),8.10 (d, J=2.1 Hz, 1H), 8.02 (d, J=2.3 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H),7.60 (s, 1H), 7.48 (dd, J=8.5, 0.9 Hz, 2H), 7.37 (dd, J=8.5, 2.1 Hz,1H), 7.29 (dd, J=8.2, 7.6 Hz, 2H), 6.96-6.99 (m, 1H), 6.75 (s, 2H), 3.44(s, 6H)

Example 5

6-amino-5-{5-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]-1-benzothien-2-yl}-N-[dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamide

In a manner similar to that described in Example 1,6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamideand 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene were converted tothe title compound.

¹H NMR (DMSO-d₆) δ: 9.30 (br. s., 1H), 9.08 (br. s., 1H), 8.61 (d, J=2.1Hz, 1H), 8.16 (d, J=2.3 Hz, 1H), 8.11 (d, J=1.8 Hz, 1H), 8.02 (d, J=2.1Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.60-7.67 (m, 3H), 7.39 (dd, J=8.8, 2.1Hz, 1H), 6.76 (s, 2H), 3.44 (s, 6H).

Example 6

6-amino-N-[dimethyl(oxido)-λ⁴-sulfanylidene]-5-{5-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]-1-benzothien-2-yl}nicotinamide

In a manner similar to that described in Example 1,6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamideand 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene were converted tothe title compound.

¹H NMR (DMSO-d₆) δ: 9.31 (s, 1H), 8.93 (d, J=2.6 Hz, 1H), 8.67 (dd,J=7.3, 2.1 Hz, 1H), 8.61 (d, J=2.1 Hz, 1H), 8.15 (d, J=2.1 Hz, 1H), 8.03(d, J=2.1 Hz, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.62 (s, 1H), 7.51 (dd,J=10.6, 8.8 Hz, 1H), 7.38-7.41 (m, 1H), 7.36 (dd, J=8.5, 2.1 Hz, 1H),6.77 (s, 2H), 3.44 (s, 6H).

Example 7

methyl6-amino-5-{5-[({[3-(trifluoromethyl)phenyl]amino}carbonyl)amino]-1-benzothien-2-yl}nicotinate

In a manner similar to that described in Example 11, methyl6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and1-isocyanato-3-(trifluoromethyl)benzene were converted to the titlecompound.

¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.94 (s, 1H), 8.57 (d, J=2.3 Hz, 1H),8.13 (d, J=2.1 Hz, 1H), 8.06 (t, J=1.5 Hz, 1H), 7.94 (d, J=2.3 Hz, 1H),7.90 (d, J=8.5 Hz, 1H), 7.63 (s, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.52 (t,J=7.9 Hz, 1H), 7.40 (dd, J=8.5, 2.1 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H),7.01 (br. s., 2H), 3.81 (s, 3H).

Example 8

methyl6-amino-5-{5-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]-1-benzothien-2-yl}nicotinate

In a manner similar to that described in Example 11, methyl6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene were converted to thetitle compound.

¹H NMR (DMSO-d₆) δ: 9.31 (s, 1H), 8.93 (d, J=2.6 Hz, 1H), 8.67 (dd,J=7.3, 2.1 Hz, 1H), 8.58 (d, J=2.1 Hz, 1H), 8.16 (d, J=2.1 Hz, 1H), 7.94(d, J=2.3 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.65 (s, 1H), 7.51 (dd,J=10.7, 8.9 Hz, 1H), 7.38-7.42 (m, 1H), 7.37 (dd, J=8.7, 2.2 Hz, 1H),7.02 (br. s., 2H), 3.81 (s, 3H).

Example 9

methyl6-amino-5-{5-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]-1-benzothien-2-yl}nicotinate

In a manner similar to that described in Example 11, methyl6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and1-chloro-4-isocyanato-2-(trifluoromethyl)benzene were converted to thetitle compound.

¹H NMR (DMSO-d₆) δ: 9.20 (s, 1H), 9.00 (s, 1H), 8.57 (d, J=2.3 Hz, 1H),8.16 (d, J=2.3 Hz, 1H), 8.12 (d, J=2.1 Hz, 1H), 7.94 (d, J=2.3 Hz, 1H),7.90 (d, J=8.8 Hz, 1H), 7.61-7.67 (m, 3H), 7.40 (dd, J=8.5, 2.1 Hz, 1H),7.01 (br. s., 2H), 3.81 (s, 3H).

Example 10

methyl6-amino-5-[5-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinate

In a manner similar to that described in Example 11, methyl6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and1-fluoro-2-isocyanato-4-methylbenzene were converted to the titlecompound.

¹H NMR (DMSO-d₆) δ: 9.19 (s, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.50 (d, J=2.6Hz, 1H), 8.13 (d, J=2.1 Hz, 1H), 8.03 (dd, J=7.9, 1.8 Hz, 1H), 7.94 (d,J=2.1 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.62 (s, 1H), 7.36 (dd, J=8.5,2.1 Hz, 1H), 7.11 (dd, J=11.3, 8.4 Hz, 1H), 7.01 (br. s., 2H), 6.79-6.82(m, 1H), 3.81 (s, 3H), 2.28 (s, 3H)

Preparation 3

methyl6-amino-5-{5-[(tert-butoxycarbonyl)amino]-1-benzothien-2-yl}nicotinate

To the degassed mixture of methyl 6-amino-5-iodonicotinate (4.17 g, 15mmol, 1 eq),{[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[b]thiophen-5-yl]-carbamicacid tert-butyl ester} (6.47 g, 1.15 eq), and aq sodium carbonate (2M,22.5 mL, 3 eq) in dioxane (30 mL) was added Ph₃P (393 mg, 0.1 eq) andPd(OAc)₂ (340 mg, 0.1 eq). The mixture was heated to 50° C. withvigorous stirring for 45 minutes. The reaction mixture was thenpartitioned between aq NH₄Cl and EtOAc. The organic layer was isolated,washed with sat aq NaHCO₃, brine, and finally dried with anhydroussodium sulfate. The upper solution-layer was decanted, concentrated, andthe solid residue was treated with EtOAc-Hex (1:4) with stirring at roomtemperature for 3 hours. methyl6-amino-5-{5-[(tert-butoxycarbonyl)amino]-1-benzothien-2-yl}nicotinatewas obtained upon filtration as a slightly green-yellowish solid.

¹H NMR (DMSO-d₆) δ: 9.48 (br. s., 1H), 8.56 (d, J=2.1 Hz, 1H), 8.08 (br.s., 1H), 7.93 (d, J=2.3 Hz, 1H), 7.84 (d, J=8.5 Hz, 1H), 7.59 (s, 1H),7.41 (dd, J=8.8, 2.1 Hz, 1H), 7.00 (br. s., 2H), 3.81 (s, 3H), 1.50 (s,9H)

Preparation 4

methyl 6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate

To the above obtained crude solid of methyl6-amino-5-{5-[(tert-butoxycarbonyl)amino]-1-benzothien-2-yl}nicotinate(15 mmol, 1 eq) in dichloromethane (25 mL) at 0° C. was added dropwisetrifluoroacetic acid (11.7 mL, 10 eq). During this process the reactionmixture became a brown solution. After the reaction was stirred at 0° C.for 10 minutes and at room temperature for 5 hours, it was slowly pouredinto an ice-cooled saturated aqueous sodium bicarbonate solution withstirring. When all the bubbling ceased, the mixture was extracted withdichloromethane, which was washed with brine and dried with anhydroussodium sulfate. The upper brown solution was decanted, concentrated to alesser amount, and the occurring solid mixture was treated withEtOAc-Hex (1:1). A green-yellowish solid was obtained upon filtrationwhich was further subject to chromatography (MeOH-DCM 1:100 to 1:20).The corresponding product fractions were collected, concentrated, andtriturated with EtOAc-Hex (1:4) giving methyl6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate as a slightly yellowsolid in amount of 3.48 g upon filtration with a yield of 78% for twosteps.

¹H NMR (DMSO-d₆) δ: 8.54 (d, J=2.1 Hz, 1H), 7.91 (d, J=2.1 Hz, 1H), 7.58(d, J=8.5 Hz, 1H), 7.40 (s, 1H), 6.97 (d, J=2.1 Hz, 1H), 6.94 (br. s.,2H), 6.74 (dd, J=8.5, 2.1 Hz, 1H), 5.13 (s, 2H), 3.80 (s, 3H)

Example 11

methyl6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinate

To the solution of methyl6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate (120 mg, 0.4 mmol. 1 eq)in anhydrous THF (4 mL) at room temperature was added dropwisem-tolylisocyanate (0.051 mL, 1 eq). After the reaction was stirred atroom temperature for 4 hours, the solid appeared in the reaction wasdirectly filtered to give methyl6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinateas a white solid in amount of 84 mg.

¹H NMR (DMSO-d₆) δ: 8.78 (s, 1H), 8.61 (s, 1H), 8.57 (d, J=2.1 Hz, 1H),8.11 (d, J=2.1 Hz, 1H), 7.94 (d, J=2.3 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H),7.61 (s, 1H), 7.38 (dd, J=8.7, 2.2 Hz, 1H), 7.32 (s, 1H), 7.25 (d, J=8.2Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 7.01 (br. s., 2H), 6.80 (d, J=7.3 Hz,1H), 3.81 (s, 3H), 2.29 (s, 3H).

Example 12

methyl6-amino-5-[5-({[(3-chloro-4-fluorophenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinate

In a manner similar to that described in Example 11, methyl6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and2-chloro-1-fluoro-4-isocyanatobenzene are converted to the titlecompound.

¹H NMR (DMSO-d₆) δ: 8.90 (s, 1H), 8.90 (s, 1H), 8.57 (d, J=2.3 Hz, 1H),8.09 (d, J=2.1 Hz, 1H), 7.94 (d, J=2.1 Hz, 1H), 7.89 (d, J=8.5 Hz, 1H),7.83 (dd, J=6.9, 1.9 Hz, 1H), 7.62 (s, 1H), 7.39 (dd, J=8.8, 2.1 Hz,1H), 7.31-7.35 (m, 2H), 7.01 (br. s., 2H), 3.81 (s, 3H).

Example 13

methyl6-amino-5-[5-({[(4-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinate

In a manner similar to that described in Example 11, methyl6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and1-isocyanato-4-methylbenzene are converted to the title compound.

¹H NMR (DMSO-d₆) δ: 8.75 (s, 1H), 8.57 (d, J=2.1 Hz, 2H), 8.09 (d, J=2.1Hz, 1H), 7.94 (d, J=2.3 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.61 (s, 1H),7.34-7.39 (m, 3H), 7.09 (d, J=8.2 Hz, 2H), 7.01 (br. s., 2H), 3.81 (s,3H), 2.25 (s, 3H).

Example 14

methyl6-amino-5-[5-({[(2-fluorophenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinate

In a manner similar to that described in Example 11, methyl6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and1-fluoro-2-isocyanatobenzene are converted to the title compound.

¹H NMR (DMSO-d₆) δ: 9.21 (s, 1H), 8.57-8.59 (m, 2H), 8.19 (td, J=8.3,1.6 Hz, 1H), 8.12 (d, J=2.1 Hz, 1H), 7.94 (d, J=2.1 Hz, 1H), 7.90 (d,J=8.5 Hz, 1H), 7.63 (s, 1H), 7.37 (dd, J=8.8, 2.1 Hz, 1H), 7.25 (ddd,J=11.7, 8.1, 1.3 Hz, 1H), 7.15 (t, J=7.8 Hz, 1H), 6.99-7.04 (m, 3H),3.81 (s, 3H).

Example 15

methyl6-amino-5-{5-[(anilinocarbonyl)amino]-1-benzothien-2-yl}nicotinate

In a manner similar to that described in Example 11, methyl6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and isocyanatobenzeneare converted to the title compound.

¹H NMR (DMSO-d₆) □: 8.81 (s, 1H), 8.69 (s, 1H), 8.57 (d, J=2.3 Hz, 1H),8.11 (d, J=2.1 Hz, 1H), 7.94 (d, J=2.3 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H),7.62 (s, 1H), 7.46-7.49 (m, 2H), 7.38 (dd, J=8.5, 2.1 Hz, 1H), 7.27-7.31(m, 2H), 7.01 (br. s., 2H), 6.98 (tt, J=7.3, 1.0 Hz, 1H), 3.81 (s, 3H).

Example 16

methyl6-amino-5-[5-({[(2,4-difluorophenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinate

In a manner similar to that described in Example 11, methyl6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and2,4-difluoro-1-isocyanatobenzene are converted to the title compound.

¹H NMR (DMSO-d₆) δ: 9.15 (s, 1H), 8.57 (d, J=2.3 Hz, 1H), 8.53 (d, J=2.1Hz, 1H), 8.09-8.14 (m, 2H), 7.94 (d, J=2.1 Hz, 1H), 7.89 (d, J=8.5 Hz,1H), 7.63 (s, 1H), 7.37 (dd, J=8.5, 2.1 Hz, 1H), 7.32 (ddd, J=11.5, 8.7,2.9 Hz, 1H), 7.04-7.08 (m, 1H), 7.01 (br. s., 2H), 3.81 (s, 3H).

Example 17

6-amino-5-[5-({[(3-chloro-4-fluorophenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinicacid

In a manner similar to that described in Example 19, methyl6-amino-5-[5-({[(3-chloro-4-fluorophenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinatewas converted to the title compound.

¹H NMR (DMSO-d₆) δ: 12.65 (br. s., 1H), 8.96 (d, J=3.5 Hz, 2H), 8.55 (d,J=2.3 Hz, 1H), 8.09 (d, J=2.1 Hz, 1H), 7.95 (d, J=2.3 Hz, 1H), 7.89 (d,J=8.8 Hz, 1H), 7.80-7.86 (m, 1H), 7.62 (s, 1H), 7.39 (dd, J=8.8, 2.1 Hz,1H), 7.30-7.36 (m, 2H), 6.99 (br. s., 2H).

Example 18

6-amino-5-[5-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinicacid

In a manner similar to that described in Example 19, methyl6-amino-5-[5-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinatewas converted to the title compound.

¹H NMR (DMSO-d₆) δ: 12.73 (br. s., 1H), 9.27 (s, 1H), 8.51-8.58 (m, 2H),8.14 (d, J=2.1 Hz, 1H), 8.02 (dd, J=7.9, 1.8 Hz, 1H), 7.97 (d, J=2.1 Hz,1H), 7.90 (d, J=8.5 Hz, 1H), 7.63 (s, 1H), 7.37 (dd, J=8.6, 2.2 Hz, 1H),7.04-7.20 (m, 3H), 6.80 (ddd, J=7.7, 5.2, 2.1 Hz, 1H), 2.28 (s, 3H)

Example 19

6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinicacid

To the stirring mixture of methyl6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinate(420 mg, 0.972 mmol, 1 eq) in MeOH—H₂O (3:1, 20 mL) at room temperaturewas added potassium hydroxide pellets (272 mg, 5 eq) and the reactionmixture was stirred at 65° C. for total of two hours, at which time thereaction mixture became a clear yellow solution. The solution wasconcentrated under reduced pressure to remove most part of methanol. Themixture was then cooled in an ice-bath, concentrated hydrochloride wasadded dropwise, and the pH was adjusted to about 3. After the mixturewas stirred for about another 30 minutes, it was filtered through aBuchner funnel, rinsed with water, and6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinicacid was obtained as a yellow solid in quantitative yield.

¹H NMR (DMSO-d₆) δ: 9.09 (s, 1H), 8.88 (s, 1H), 8.55 (d, J=2.1 Hz, 1H),8.14 (d, J=2.1 Hz, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H),7.63 (s, 1H), 7.29-7.45 (m, 4H), 7.26 (d, J=8.2 Hz, 1H), 7.12-7.19 (m,1H), 6.79 (d, J=7.3 Hz, 1H), 2.28 (s, 3H)

Example 20

6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinamide

To a seal tube containing6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinic(84 mg, 0.2 mmol, 1 eq), DMAP (5 mg, 0.2 eq), and EDCI (46.1 mg, 1.2 eq)in anhydrous THF (3 mL) at room temperature, gaseous ammonia was bubbledthrough for about 5 minutes. The tube was quickly capped and thereaction was heated at 60° C. for one hour.

TLC indicated the reaction did not proceed.

After the reaction was cooled to room temperature, to the reactionmixture was added anhydrous DMF (3 mL), diisopropylethylamine (0.2 mL, 5eq), ammonium chloride (32.1 mg, 3 eq), and(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(97.3 mg, 1.1 eq). After the reaction was stirred at 60° C. for 30minutes, it was partitioned between ethyl acetate and aqueous ammoniumchloride. The organic layer was isolated, washed with saturated aqueoussodium bicarbonate, brine, and dried with anhydrous sodium sulfate. Theclear solution was decanted, concentrated, the solid residue was subjectto a gradient column chromatography (from DCM to MeOH-DCM 1:1).6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinamidewas obtained as white solid in two portions, 38 mg from thechromatography fractions and 16 mg from a remainder on top of thesyringe column. Both were confirmed by proton NMR.

¹H NMR (DMSO-d₆) δ: 8.81 (s, 1H), 8.63 (s, 1H), 8.55 (d, J=2.1 Hz, 1H),8.08 (d, J=1.8 Hz, 1H), 8.03 (d, J=2.3 Hz, 1H), 7.95-6.88 (br. s., 2H),7.86 (d, J=8.5 Hz, 1H), 7.59 (s, 1H), 7.39 (dd, J=8.8, 2.1 Hz, 1H), 7.32(s, 1H), 7.23-7.29 (m, 1H), 7.13-7.19 (m, 1H), 6.80 (d, J=7.3 Hz, 1H),6.48 (s, 2H), 2.29 (s, 3H).

Example 21

methyl4-[({6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]pyridin-3-yl}carbonyl)amino]butanoate

In a manner similar to that described in Example 22,6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinicacid was converted to the title compound.

¹H NMR (DMSO-d₆) δ: 8.80 (s, 1H), 8.62 (s, 1H), 8.52 (d, J=2.3 Hz, 1H),8.33 (t, J=5.6 Hz, 1H), 8.10 (d, J=2.1 Hz, 1H), 8.01 (d, J=2.3 Hz, 1H),7.88 (d, J=8.8 Hz, 1H), 7.60 (s, 1H), 7.37 (dd, J=8.8, 2.1 Hz, 1H), 7.32(s, 1H), 7.22-7.28 (m, 1H), 7.13-7.20 (m, 1H), 6.80 (d, J=7.6 Hz, 1H),6.61 (s, 2H), 3.58 (s, 3H), 3.21-3.30 (m, 2H), 2.37 (t, J=7.3 Hz, 2H),2.29 (s, 3H), 1.77 (quin, J=7.1 Hz, 2H)

Example 22

methyl6-[({6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]pyridin-3-yl}carbonyl)amino]hexanoate

The reaction mixture of6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinicacid (84 mg, 0.2 mmol, 1 eq), methyl 6-aminohexanoate hydrochloride(43.7 mg, 1.2 eq), DMAP (5 mg, 0.2 eq), and EDCI (46.1 mg, 1.2 eq) inanhydrous 1,2-dichloroethane (3 mL) was stirred and heated at 50° C. for2 hours. It was then diluted with ethyl acetate, washed sequentiallywith aqueous NH₄Cl, saturated aqueous NaHCO₃, and brine, and dried withanhydrous sodium sulfate. The upper clear solution was decanted,concentrated, and the solid residue was triturated with EtOAc-Hex (3:1)yielding methyl6-[({6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]pyridin-3-yl}carbonyl)amino]hexanoateas a white solid in amount of 83 mg.

¹H NMR (DMSO-d₆) δ: 8.79 (s, 1H), 8.62 (s, 1H), 8.51 (d, J=2.3 Hz, 1H),8.29 (t, J=5.6 Hz, 1H), 8.10 (d, J=1.8 Hz, 1H), 8.00 (d, J=2.3 Hz, 1H),7.88 (d, J=8.5 Hz, 1H), 7.60 (s, 1H), 7.37 (dd, J=8.8, 2.1 Hz, 1H), 7.32(s, 1H), 7.22-7.28 (m, 1H), 7.13-7.20 (m, 1H), 6.80 (d, J=7.3 Hz, 1H),6.60 (s, 2H), 3.57 (s, 3H), 3.22 (q, J=6.4 Hz, 2H), 2.26-2.35 (m, 5H),1.53 (tt, J=14.5, 7.3 Hz, 4H), 1.26-1.36 (m, 2H).

Example 23

1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-1-benzothien-5-yl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea

In a manner similar to that described in Example 29,3-(5-amino-1-benzothien-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amineand 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene are converted tothe title compound.

¹H NMR (DMSO-d₆) δ: 9.30 (s, 1H), 8.92 (d, J=2.6 Hz, 1H), 8.67 (dd,J=7.3, 2.1 Hz, 1H), 8.24 (d, J=1.8 Hz, 1H), 8.12 (d, J=1.8 Hz, 1H), 7.89(d, J=8.5 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.61 (s, 1H), 7.46-7.55 (m,1H), 7.33-7.43 (m, 2H), 6.53 (s, 2H), 1.28 (s, 12H).

Example 24

1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-1-benzothien-5-yl}-3-[3-(trifluoromethyl)phenyl]urea

In a manner similar to that described in Example 29,3-(5-amino-1-benzothien-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amineand 1-isocyanato-3-(trifluoromethyl)benzene are converted to the titlecompound.

¹H NMR (DMSO-d₆) δ: 9.07 (s, 1H), 8.92 (s, 1H), 8.24 (d, J=1.8 Hz, 1H),8.09 (d, J=1.8 Hz, 1H), 8.06 (s, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.69 (d,J=1.8 Hz, 1H), 7.56-7.62 (m, 2H), 7.48-7.55 (m, 1H), 7.39 (dd, J=8.6,2.2 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 6.53 (s, 2H), 1.28 (s, 12H)

Example 25

1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-1-benzothien-5-yl}-3-[4-chloro-3-(trifluoromethyl)phenyl]urea

In a manner similar to that described in Example 29,3-(5-amino-1-benzothien-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amineand 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene are converted tothe title compound.

¹H NMR (DMSO-d₆) δ: 9.19 (s, 1H), 8.98 (s, 1H), 8.24 (d, J=1.8 Hz, 1H),8.16 (d, J=2.1 Hz, 1H), 8.08 (d, J=2.1 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H),7.69 (d, J=1.8 Hz, 1H), 7.62-7.66 (m, 2H), 7.59 (s, 1H), 7.39 (dd,J=8.5, 2.1 Hz, 1H), 6.53 (s, 2H), 1.28 (s, 12H)

Example 26

1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-1-benzothien-5-yl}-3-(2-fluoro-5-methylphenyl)urea

In a manner similar to that described in Example 29,3-(5-amino-1-benzothien-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amineand 1-fluoro-2-isocyanato-4-methylbenzene are converted to the titlecompound.

¹H NMR (DMSO-d₆) δ: 9.18 (s, 1H), 8.50 (d, J=2.6 Hz, 1H), 8.24 (d, J=1.8Hz, 1H), 8.09 (d, J=2.1 Hz, 1H), 8.03 (dd, J=7.9, 1.8 Hz, 1H), 7.87 (d,J=8.8 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.58 (s, 1H), 7.36 (dd, J=8.8,2.1 Hz, 1H), 7.11 (dd, J=11.4, 8.2 Hz, 1H), 6.77-6.84 (m, 1H), 6.53 (s,2H), 2.28 (s, 3H), 1.28 (s, 12H)

Example 27

1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-1-benzothien-5-yl}-3-(3-chloro-4-fluorophenyl)urea

In a manner similar to that described in Example 29,3-(5-amino-1-benzothien-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amineand 2-chloro-1-fluoro-4-isocyanatobenzene are converted to the titlecompound.

¹H NMR (DMSO-d₆) δ: 8.89 (s, 1H), 8.88 (s, 1H), 8.24 (d, J=1.8 Hz, 1H),8.06 (d, J=2.1 Hz, 1H), 7.81-7.89 (m, 2H), 7.69 (d, J=1.8 Hz, 1H), 7.58(s, 1H), 7.31-7.41 (m, 3H), 6.52 (s, 2H), 1.28 (s, 12H)

Example 28

1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-1-benzothien-5-yl}-3-(3-ethylphenyl)urea

In a manner similar to that described in Example 29,3-(5-amino-1-benzothien-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amineand 1-ethyl-3-isocyanatobenzene are converted to the title compound.

¹H NMR (DMSO-d₆) δ: 8.76 (s, 1H), 8.62 (s, 1H), 8.24 (d, J=1.8 Hz, 1H),8.08 (d, J=2.1 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H),7.58 (s, 1H), 7.34-7.39 (m, 2H), 7.23-7.30 (m, 1H), 7.15-7.23 (m, 1H),6.83 (d, J=7.3 Hz, 1H), 6.52 (s, 2H), 2.58 (q, J=7.5 Hz, 2H), 1.28 (s,12H), 1.19 (t, J=7.6 Hz, 3H)

Example 29

1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-1-benzothien-5-yl}-3-(3-methylphenyl)urea

To the solution of3-(5-amino-1-benzothien-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(734.6 mg, 2 mmol. 1 eq) in anhydrous THF (10 mL) at room temperaturewas added dropwise m-tolylisocyanate (0.251 mL, 1 eq). After thereaction was stirred at room temperature for 4 hours, it was partitionedbetween ethyl acetate and aqueous ammonium chloride. The organic layerwas isolated, washed with saturated aqueous sodium bicarbonate, brine,and dried with anhydrous sodium sulfate. The upper solution layer wasdecanted, concentrated, and the solid residue was subject to a gradientcolumn chromatography (DCM to MeOH-DCM 1:5). The products' fractionswere collected, concentrated, the solid was triturated with EtOAc-Hex(1:7) yielding1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-1-benzothien-5-yl}-3-(3-methylphenyl)ureaas a white powder upon filtration in amount of 407 mg.

¹H NMR (DMSO-d₆) δ: 8.77 (s, 1H), 8.60 (s, 1H), 8.24 (d, J=1.8 Hz, 1H),8.07 (d, J=1.8 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H),7.57 (s, 1H), 7.37 (dd, J=8.6, 2.2 Hz, 1H), 7.32 (s, 1H), 7.22-7.28 (m,1H), 7.13-7.20 (m, 1H), 6.79 (d, J=7.3 Hz, 1H), 6.52 (s, 2H), 2.29 (s,3H), 1.28 (s, 12H).

Example 30

1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-1-benzothien-5-yl}-3-phenylurea

In a manner similar to that described in Example 29,3-(5-amino-1-benzothien-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amineand isocyanatobenzene are converted to the title compound.

¹H NMR (DMSO-d₆) δ: 8.78 (s, 1H), 8.68 (s, 1H), 8.24 (d, J=1.5 Hz, 1H),8.07 (d, J=1.5 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H),7.58 (s, 1H), 7.48 (d, J=7.6 Hz, 2H), 7.38 (dd, J=8.8, 1.8 Hz, 1H), 7.29(t, J=7.8 Hz, 2H), 6.94-7.01 (m, 1H), 6.53 (s, 2H), 1.28 (s, 12H).

Example 31

{6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]pyridin-3-yl}boronicacid

To the solution of1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-1-benzothien-5-yl}-3-(3-methylphenyl)urea(500 mg, 1 mmol, 1 eq) in tetrahydrofuran (6 mL) at room temperature wasadded dropwise aqueous HCl (3 N, 6 mL) and the reaction was stirred atroom temperature for 4 hours. The reaction mixture was filtered directlythrough a Buchner funnel, rinsed with isopropanol, followed byi-PrOH—H₂O (1:1) to give{6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]pyridin-3-yl}boronicacid as a white solid in amount of 384 mg.

¹H NMR (DMSO-d₆) δ: 9.26 (s, 1H), 9.02 (s, 1H), 8.54 (br. s., 2H), 8.27(dd, J=12.0, 1.5 Hz, 2H), 8.20 (d, J=2.1 Hz, 1H), 8.16 (br. s., 2H),7.94 (d, J=8.8 Hz, 1H), 7.65 (s, 1H), 7.42 (dd, J=8.8, 2.1 Hz, 1H), 7.32(s, 1H), 7.27 (d, J=8.5 Hz, 1H), 7.12-7.19 (m, 1H), 6.79 (d, J=7.3 Hz,1H), 2.28 (s, 3H).

Example 32

(6-amino-5-{5-[(anilinocarbonyl)amino]-1-benzothien-2-yl}pyridin-3-yl)boronicacid

In a manner similar to that described in Example 31,1-{2-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-1-benzothien-5-yl}-3-phenylureawas converted to the title compound.

¹H NMR (DMSO-d₆) δ: 9.13 (s, 1H), 8.97 (s, 1H), 8.52 (br. s., 2H), 8.26(dd, J=6.4, 1.5 Hz, 2H), 8.19 (d, J=1.8 Hz, 1H), 8.04 (br. s., 2H), 7.94(d, J=8.8 Hz, 1H), 7.65 (s, 1H), 7.48 (d, J=7.3 Hz, 2H), 7.41 (dd,J=8.8, 2.1 Hz, 1H), 7.29 (t, J=8.1 Hz, 2H), 6.94-7.01 (m, 1H)

Example 33

6-amino-N-[dimethyl(oxido)-λ⁴-sulfanylidene]-5-{5-[(3-methyl-2-furoyl)amino]-1-benzothien-2-yl}nicotinamide

To the mixture of6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamide(72 mg, 0.2 mmol, 1 eq) and 3-methylfuranylcarboxylic acid (25.2 mg, 1eq) in dichloroethane (2 mL) at 50° C. was added catalytic amount ofDMAP and EDCI (46.1 mg, 1.2 eq). The reaction was stirred at thattemperature for 1 h and then at room temperature for 20 h. It was thenpartitioned between EtOAc and saturated aq NaHCO₃. The organic layer wasfurther washed with brine and then dried with anhydrous sodium sulfate.The organic layer was decanted, concentrated, and the residue wassubject to a gradient column chromatography (EtOAc-Hex 2:1 to neatEtOAc) rendering6-amino-N-[dimethyl(oxido)-λ⁴-sulfanylidene]-5-{5-[(3-methyl-2-furoyl)amino]-1-benzothien-2-yl}nicotinamideas white solid in amount of 90 mg (96%).

¹H NMR (DMSO-d₆) δ: 10.17 (s, 1H), 8.61 (d, J=2.1 Hz, 1H), 8.41 (d,J=1.8 Hz, 1H), 8.03 (d, J=2.1 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.81 (d,J=1.5 Hz, 1H), 7.71 (dd, J=8.8, 2.1 Hz, 1H), 7.62 (s, 1H), 6.76 (s, 2H),6.61 (d, J=1.5 Hz, 1H), 3.44 (s, 6H), 2.37 (s, 3H)

Example 34

6-amino-5-(5-{[4-chloro-3-(trifluoromethyl)benzoyl]amino}-1-benzothien-2-yl)-N-[dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamide

In a manner similar to that described in Example 33,6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamideand 4-chloro-3-(trifluoromethyl)benzoic acid were converted to the titlecompound.

¹H NMR (DMSO-d₆) δ: 10.66 (s, 1H), 8.62 (d, J=2.1 Hz, 1H), 8.43 (d,J=1.8 Hz, 1H), 8.38 (d, J=1.8 Hz, 1H), 8.31 (dd, J=8.2, 1.8 Hz, 1H),8.04 (d, J=2.1 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.95 (d, J=8.2 Hz, 1H),7.70 (dd, J=8.5, 2.1 Hz, 1H), 7.68 (s, 1H), 6.79 (s, 2H), 3.44 (s, 6H)

Example 35

6-amino-N-[dimethyl(oxido)-λ⁴-sulfanylidene]-5-{5-[(2-fluoro-5-methylbenzoyl)amino]-1-benzothien-2-yl}nicotinamide

In a manner similar to that described in Example 33,6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamideand 2-fluoro-5-methylbenzoic acid were converted to the title compound.

¹H NMR (DMSO-d₆) δ: 10.50 (s, 1H), 8.61 (d, J=2.3 Hz, 1H), 8.39 (d,J=1.8 Hz, 1H), 8.04 (d, J=2.3 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.66 (s,1H), 7.62 (dd, J=8.7, 1.9 Hz, 1H), 7.50 (dd, J=6.5, 1.8 Hz, 1H),7.36-7.40 (m, 1H), 7.22-7.26 (m, 1H), 6.78 (s, 2H), 3.44 (s, 6H), 2.36(s, 3H)

Example 36

6-amino-5-[5-(benzoylamino)-1-benzothien-2-yl]-N-[dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamide

In a manner similar to that described in Example 33,6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamideand benzoic acid were converted to the title compound.

¹H NMR (DMSO-d₆) δ: 10.39 (s, 1H), 8.61 (d, J=2.1 Hz, 1H), 8.42 (d,J=1.8 Hz, 1H), 8.04 (d, J=2.1 Hz, 1H), 8.00 (d, J=7.0 Hz, 2H), 7.95 (d,J=8.8 Hz, 1H), 7.72 (dd, J=8.7, 1.9 Hz, 1H), 7.66 (s, 1H), 7.59-7.63 (m,1H), 7.53-7.57 (m, 2H), 6.78 (s, 2H), 3.44 (s, 6H)

Example 37

6-amino-N-[dimethyl(oxido)-λ⁴-sulfanylidene]-5-{5-[(3-methylbenzoyl)amino]-1-benzothien-2-yl}nicotinamide

In a manner similar to that described in Example 33,6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamideand 3-methylbenzoic acid were converted to the title compound.

¹H NMR (DMSO-d₆) δ: 10.34 (s, 1H), 8.61 (d, J=2.1 Hz, 1H), 8.41 (d,J=1.5 Hz, 1H), 8.04 (d, J=2.1 Hz, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.81 (s,1H), 7.78 (d, J=6.7 Hz, 1H), 7.71 (dd, J=8.5, 1.8 Hz, 1H), 7.65 (s, 1H),7.40-7.44 (m, 2H), 6.78 (s, 2H), 3.44 (s, 6H), 2.42 (s, 3H)

Example 38

6-amino-N-[dimethyl(oxido)-λ⁴-sulfanylidene]-5-(5-{[2-fluoro-5-(trifluoromethyl)benzoyl]amino}-1-benzothien-2-yl)nicotinamide

In a manner similar to that described in Example 33,6-amino-5-(5-amino-1-benzothien-2-yl)-N-[dimethyl(oxido)-λ⁴-sulfanylidene]nicotinamideand 2-fluoro-5-(trifluoromethyl)benzoic acid were converted to the titlecompound.

¹H NMR (DMSO-d₆) δ: 10.73 (s, 1H), 8.61 (d, J=2.3 Hz, 1H), 8.37 (d,J=2.1 Hz, 1H), 8.10 (dd, J=6.2, 2.1 Hz, 1H), 8.04 (d, J=2.1 Hz, 1H),7.99-8.02 (m, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.68 (s, 1H), 7.64 (t, J=9.1Hz, 1H), 7.61 (dd, J=8.8, 2.1 Hz, 1H), 6.79 (s, 2H), 3.44 (s, 6H)

Example 39

methyl6-amino-5-{5-[(3-methyl-2-furoyl)amino]-1-benzothien-2-yl}nicotinate

To the mixture of methyl 6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate(120 mg, 0.4 mmol, 1 eq) and 3-methylfuranylcarboxylic acid (50.4 mg, 1eq) in 1,2-dichloroethane (3 mL) at 60° C. was added catalytic amount ofDMAP (10 mg, 0.2 eq) and EDCI (92.2 mg, 1.2 eq). The reaction wasstirred at that temperature for 2 h and then partitioned between EtOAcand saturated aq NaHCO₃. The organic layer was further washed with brineand then dried with anhydrous sodium sulfate. The organic layer wasdecanted, concentrated, and the solid residue which was treated withethyl acetate with stirring at room temperature for an hour. Methyl6-amino-5-{5-[(3-methyl-2-furoyl)amino]-1-benzothien-2-yl}nicotinate wasobtained upon filtration as a white solid in amount of 128 mg.

¹H NMR (DMSO-d₆) δ: 10.18 (s, 1H), 8.58 (d, J=2.3 Hz, 1H), 8.42 (d,J=2.1 Hz, 1H), 7.95 (d, J=2.1 Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.81 (d,J=1.8 Hz, 1H), 7.72 (dd, J=8.8, 2.1 Hz, 1H), 7.64 (s, 1H), 7.02 (br. s.,2H), 6.61 (d, J=1.5 Hz, 1H), 3.81 (s, 3H), 2.37 (s, 3H)

Example 40

methyl6-amino-5-{5-[(3-methylbenzoyl)amino]-1-benzothien-2-yl}nicotinate

In a manner similar to that described in Example 39, methyl6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and 3-methylbenzoic acidwere converted to the title compound.

¹H NMR (DMSO-d₆) δ: 10.34 (s, 1H), 8.58 (d, J=2.1 Hz, 1H), 8.42 (d,J=1.8 Hz, 1H), 7.94-7.97 (m, 2H), 7.81 (s, 1H), 7.78 (d, J=6.7 Hz, 1H),7.72 (dd, J=8.7, 1.9 Hz, 1H), 7.68 (s, 1H), 7.40-7.45 (m, 2H), 7.03 (br.s., 2H), 3.81 (s, 3H), 2.42 (s, 3H)

Example 41

methyl6-amino-5-{5-[(2-fluoro-5-methylbenzoyl)amino]-1-benzothien-2-yl}nicotinate

In a manner similar to that described in Example 39, methyl6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and2-fluoro-5-methylbenzoic acid were converted to the title compound.

¹H NMR (DMSO-d₆) δ: 10.51 (s, 1H), 8.58 (d, J=2.1 Hz, 1H), 8.39 (d,J=1.2 Hz, 1H), 7.94-7.97 (m, 2H), 7.68 (s, 1H), 7.63 (dd, J=8.7, 1.9 Hz,1H), 7.50 (dd, J=6.5, 1.5 Hz, 1H), 7.36-7.40 (m, 1H), 7.24 (t, J=9.2 Hz,1H), 7.03 (br. s., 2H), 3.81 (s, 3H), 2.36 (s, 3H)

Example 42

methyl 6-amino-5-[5-(benzoylamino)-1-benzothien-2-yl]nicotinate

In a manner similar to that described in Example 39, methyl6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and benzoic acid wereconverted to the title compound.

¹H NMR (DMSO-d₆) δ: 10.39 (s, 1H), 8.58 (d, J=2.3 Hz, 1H), 8.43 (d,J=1.8 Hz, 1H), 8.00 (d, J=7.0 Hz, 2H), 7.96 (dd, J=5.6, 3.2 Hz, 2H),7.73 (dd, J=8.8, 2.1 Hz, 1H), 7.68 (s, 1H), 7.59-7.63 (m, 1H), 7.53-7.58(m, 2H), 7.04 (br. s., 2H), 3.81 (s, 3H)

Example 43

methyl6-amino-5-{5-[(3-chloro-4-fluorobenzoyl)amino]-1-benzothien-2-yl}nicotinate

In a manner similar to that described in Example 39, methyl6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and3-chloro-4-fluorobenzoic acid were converted to the title compound.

¹H NMR (DMSO-d₆) δ: 10.49 (s, 1H), 8.58 (d, J=2.1 Hz, 1H), 8.39 (d,J=1.8 Hz, 1H), 8.25 (dd, J=7.2, 2.2 Hz, 1H), 8.04 (ddd, J=8.7, 4.7, 2.2Hz, 1H), 7.95-7.99 (m, 2H), 7.68-7.72 (m, 2H), 7.62 (t, J=9.0 Hz, 1H),7.04 (br. s., 2H), 3.81 (s, 3H)

Example 44

methyl6-amino-5-(5-{[2-fluoro-5-(trifluoromethyl)benzoyl]amino}-1-benzothien-2-yl)nicotinate

In a manner similar to that described in Example 39, methyl6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate and2-fluoro-5-(trifluoromethyl)benzoic acid were converted to the titlecompound.

¹H NMR (DMSO-d₆) δ: 10.74 (s, 1H), 8.58 (d, J=2.1 Hz, 1H), 8.38 (d,J=2.1 Hz, 1H), 8.10 (dd, J=6.2, 2.1 Hz, 1H), 7.99-8.02 (m, 1H), 7.98 (d,J=8.5 Hz, 1H), 7.96 (d, J=2.1 Hz, 1H), 7.70 (s, 1H), 7.64-7.67 (m, 1H),7.62 (dd, J=8.7, 1.9 Hz, 1H), 7.04 (br. s., 2H), 3.81 (s, 3H)

Example 45

methyl6-amino-5-{5-[(1-benzofuran-2-ylcarbonyl)amino]-1-benzothien-2-yl}nicotinate

In a manner similar to that described in Example 39, methyl6-amino-5-(5-amino-1-benzothien-2-yl)nicotinate andbenzofuran-2-carboxylic acid were converted to the title compound.

¹H NMR (DMSO-d₆) δ: 10.68 (s, 1H), 8.58 (d, J=2.3 Hz, 1H), 8.45 (d,J=1.8 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.96 (d, J=2.3 Hz, 1H), 7.85 (d,J=7.6 Hz, 1H), 7.81 (d, J=0.6 Hz, 1H), 7.78 (dd, J=8.7, 1.9 Hz, 1H),7.75 (d, J=8.2 Hz, 1H), 7.70 (s, 1H), 7.50-7.54 (m, 1H), 7.37-7.40 (m,1H), 7.05 (br. s., 2H), 3.81 (s, 3H)

Example 46

N-[2-(2-aminopyridin-3-yl)-1-benzothien-5-yl]-3-methylbenzamide

In a manner similar to that described in Example 39,3-(5-aminobenzo[b]thiophen-2-yl)pyridin-2-amine and 3-methylbenzoic acidwere converted to the title compound.

¹H NMR (DMSO-d₆) δ: 10.33 (s, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.02 (dd,J=4.7, 1.8 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.81 (s, 1H), 7.78 (d, J=6.7Hz, 1H), 7.69 (dd, J=8.7, 1.9 Hz, 1H), 7.64 (s, 1H), 7.60 (dd, J=7.3,1.8 Hz, 1H), 7.40-7.45 (m, 2H), 6.70 (dd, J=7.3, 5.0 Hz, 1H), 6.06 (s,2H), 2.42 (s, 3H)

Example 47

N-[2-(2-aminopyridin-3-yl)-1-benzothien-5-yl]benzamide

In a manner similar to that described in Example 39,3-(5-aminobenzo[b]thiophen-2-yl)pyridin-2-amine and benzoic acid wereconverted to the title compound.

¹H NMR (DMSO-d₆) δ: 10.38 (s, 1H), 8.40 (d, J=1.8 Hz, 1H), 7.90-8.04 (m,4H), 7.70 (dd, J=8.8, 1.8 Hz, 1H), 7.52-7.66 (m, 5H), 6.70 (dd, J=7.5,4.8 Hz, 1H), 6.07 (s, 2H)

Example 48

2-(2-aminopyridin-3-yl)-N-(3-methylphenyl)-1-benzothiophene-5-carboxamide

In a manner similar to that described in Example 51,2-(2-aminopyridin-3-yl)-1-benzothiophene-5-carboxylic acid andm-toluidine were converted to the title compound.

¹H NMR (DMSO-d₆) δ: 10.27 (s, 1H), 8.48 (s, 1H), 8.13 (d, J=8.2 Hz, 1H),8.04 (d, J=4.7 Hz, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.77 (s, 1H), 7.67 (s,1H), 7.62 (t, J=8.2 Hz, 2H), 7.25 (t, J=7.8 Hz, 1H), 6.94 (d, J=7.6 Hz,1H), 6.72 (dd, J=7.2, 5.1 Hz, 1H), 6.10 (s, 2H), 2.33 (s, 3H)

Example 49

2-(2-aminopyridin-3-yl)-N-(5-tert-butylisoxazol-3-yl)-1-benzothiophene-5-carboxamide

In a manner similar to that described in Example 51,2-(2-aminopyridin-3-yl)-1-benzothiophene-5-carboxylic acid and5-(tert-butyl)isoxazol-3-amine were converted to the title compound.

¹H NMR (DMSO-d₆) δ: 11.43 (s, 1H), 8.54 (s, 1H), 8.13 (d, J=8.5 Hz, 1H),8.04 (dd, J=4.7, 1.5 Hz, 1H), 7.98 (dd, J=8.5, 1.5 Hz, 1H), 7.75 (s,1H), 7.62 (dd, J=7.3, 1.5 Hz, 1H), 6.77 (s, 1H), 6.71 (dd, J=7.3, 4.7Hz, 1H), 6.10 (s, 2H), 1.34 (s, 9H).

Example 50

2-(2-aminopyridin-3-yl)-N-(3-methylbenzyl)-1-benzothiophene-5-carboxamide

In a manner similar to that described in Example 51,2-(2-aminopyridin-3-yl)-1-benzothiophene-5-carboxylic acid andm-tolylmethanamine were converted to the title compound.

¹H NMR (DMSO-d₆) δ: 9.11 (t, J=5.9 Hz, 1H), 8.41 (s, 1H), 8.07 (d, J=8.2Hz, 1H), 8.03 (dd, J=4.7, 1.5 Hz, 1H), 7.88 (dd, J=8.5, 1.2 Hz, 1H),7.72 (s, 1H), 7.60 (dd, J=7.6, 1.5 Hz, 1H), 7.20-7.24 (m, 1H), 7.12-7.17(m, 2H), 7.06 (d, J=7.6 Hz, 1H), 6.70 (dd, J=7.3, 5.0 Hz, 1H), 6.08 (s,2H), 4.49 (d, J=5.9 Hz, 2H), 2.29 (s, 3H)

Preparation 5

2-(dihydroxyboryl)-1-benzothiophene-5-carboxylic acid

Benzothiophene-5-carboxylic acid (2 g, 11.2 mmol, 1 eq) was dissolved inanhydrous THF (50 mL). To the solution was added dropwise tert-BuLipetane solution (1.7 M, 20 mL, 3 eq) at −78° C. for 5 minutes undernitrogen atmosphere. The reaction mixture was allowed to warm to roomtemperature, stirred for 30 minutes, and cooled to −78° C. again,followed by an addition of triisopropyl borate (3.97 mL, 1.5 eq). Thereaction was then allowed to warm to room temperature and stirred atthat temperature for one hour. To the reaction mixture was addedsaturated aqueous ammonium chloride (50 mL) and 10% aqueous potassiumhydrogensulfate solution (50 mL) to adjust pH to 2. After the mixturewas stirred at room temperature for 30 minutes, it was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous sodium sulfate. The upper solution was decanted,concentrated, and the residue was suspended in Hexane/CHCl₃/MeOH(40:4:1). The solid was filtered, rinsed with hexane.2-(dihydroxyboryl)-1-benzothiophene-5-carboxylic acid was obtained as agrayish solid in amount of 1.325 g (53%).

¹H NMR (DMSO-d₆) δ: 12.94 (br. s., 1H), 8.57 (br. s., 2H), 8.49 (s, 1H),8.05-8.09 (m, 2H), 7.90 (d, J=8.5 Hz, 1H).

Preparation 6

2-(2-aminopyridin-3-yl)-1-benzothiophene-5-carboxylic acid

To the degassed mixture of 2-amino-3-iodpyridine (1.12 g, 5.09 mmol, 1eq), 2-(dihydroxyboryl)-1-benzothiophene-5-carboxylic acid,[2-(dihydroxyboryl)-1-benzothiophene-5-carboxylic acid (1.3 g, 1.15eq)], and aqueous sodium carbonate (2M, 7.6 mL, 3 eq) in dioxane (10 mL)was added Ph₃P (267 mg, 0.2 eq) and Pd(OAc)₂ (114.3 mg, 0.1 eq). Themixture was heated to 50° C. with vigorous stirring for 30 minutes. Theyellow mixture was then partitioned between aq NH₄Cl and MeOH—CHCl₃(1:5). Some solids precipitation was observed. After the pH wascarefully adjusted to around 6, the whole mixture was filtered through aBuchner funnel to obtain a yellow solid. The solid was furthertriturated with MeOH/H₂O to give2-(2-aminopyridin-3-yl)-1-benzothiophene-5-carboxylic acid as awhite-off solid in amount of 1.18 g after dried in vacuo (86%).

¹H NMR (DMSO-d₆) δ: 12.97 (br. s., 1H), 8.46 (s, 1H), 8.09 (d, J=8.5 Hz,1H), 8.03 (d, J=3.5 Hz, 1H), 7.90 (dd, J=8.4, 1.3 Hz, 1H), 7.77 (s, 1H),7.60 (dd, J=7.3, 1.2 Hz, 1H), 6.70 (dd, J=7.3, 5.0 Hz, 1H), 6.09 (br.s., 2H)

Example 51

2-(2-aminopyridin-3-yl)-N-(2-fluoro-5-methylphenyl)-1-benzothiophene-5-carboxamide

The reaction mixture of2-(2-aminopyridin-3-yl)-1-benzothiophene-5-carboxylic acid (54 mg, 0.2mmol, 1 eq), 2-fluoro-5-methylaniline (0.048 mL, 2.1 eq), DMAP (5 mg,0.2 eq), and EDCI (46.1 mg, 1.2 eq) in anhydrous 1,2-dichloroethane (2mL) and anhydrous DMF (0.5 mL) was stirred and heated at 60° C. for 1hour. It was then diluted with ethyl acetate, washed sequentially withaqueous NH₄Cl, saturated aqueous NaHCO₃, and brine, and finally driedwith anhydrous sodium sulfate. The upper, clear solution-layer wasdecanted, concentrated, and the solid residue was subject to a gradientcolumn chromatography (EtOAc-Hex 1:4 to 1:1) to yield2-(2-aminopyridin-3-yl)-N-(2-fluoro-5-methylphenyl)-1-benzothiophene-5-carboxamideas a white solid in amount of 39.8 mg.

¹H NMR (DMSO-d₆) δ: 10.14 (s, 1H), 8.49 (s, 1H), 8.13 (d, J=8.5 Hz, 1H),8.04 (dd, J=4.7, 1.2 Hz, 1H), 7.95 (dd, J=8.5, 0.9 Hz, 1H), 7.77 (s,1H), 7.62 (dd, J=7.3, 1.2 Hz, 1H), 7.45 (d, J=6.2 Hz, 1H), 7.18 (dd,J=10.0, 8.8 Hz, 1H), 7.06-7.09 (m, 1H), 6.71 (dd, J=7.3, 5.0 Hz, 1H),6.10 (s, 2H), 2.32 (s, 3H).

Example 52

2-(2-aminopyridin-3-yl)-N-(3-chloro-4-fluorophenyl)-1-benzothiophene-5-carboxamide

In a manner similar to that described in Example 51,2-(2-aminopyridin-3-yl)-1-benzothiophene-5-carboxylic acid and3-chloro-4-fluoroaniline were converted to the title compound.

¹H NMR (DMSO-d₆) δ: 10.54 (s, 1H), 8.47 (s, 1H), 8.16 (d, J=8.5 Hz, 1H),8.13 (dd, J=6.7, 2.6 Hz, 1H), 8.04 (dd, J=4.7, 1.5 Hz, 1H), 7.94 (dd,J=8.5, 1.2 Hz, 1H), 7.76-7.79 (m, 2H), 7.62 (dd, J=7.3, 1.5 Hz, 1H),7.44 (t, J=9.1 Hz, 1H), 6.71 (dd, J=7.3, 5.0 Hz, 1H), 6.10 (s, 2H)

Example 53

methyl5-[N-({6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate

To6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinicacid (418 mg, 1 mmol, 1 equiv.) and (S)-methyl5-(S-methylsulfonimidoyl)pentanoate (232 mg, 1.2 equiv.) in anhydrousDMF (6 mL) under nitrogen atmosphere was added diisopropylethylamine(0.348 mL, 2.0 equiv.) and(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(486.5 mg, 1.1 equiv.). The reaction mixture was heated to 60° C. andstirred for 2 hours. After the reaction was cooled to room temperature,it was diluted with EtOAc and washed sequentially with saturated aqueousNaHCO₃, brine, aqueous NH₄Cl, and brine. After the organic layer wasdried (anhydrous Na₂SO₄), it was decanted, concentrated, and the brownoily residue was subject to a column chromatography (EtOAc-Hex 1:4 to6:1). methyl5-[N-({6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoatewas obtained as a yellow foam in amount of 394 mg (66%).

¹H NMR (DMSO-d₆) δ: 8.78 (s, 1H), 8.61 (s, 1H), 8.60 (s, 1H), 8.10 (d,J=2.1 Hz, 1H), 8.02 (d, J=2.3 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.59 (s,1H), 7.37 (dd, J=8.8, 2.1 Hz, 1H), 7.33 (s, 1H), 7.22-7.28 (m, 1H),7.13-7.20 (m, 1H), 6.80 (d, J=7.6 Hz, 1H), 6.75 (s, 2H), 3.55-3.63 (m,5H), 3.41 (s, 3H), 2.39 (t, J=7.2 Hz, 2H), 2.29 (s, 3H), 1.76-1.87 (m,2H), 1.63-1.74 (m, 2H)

Example 54

methyl5-[N-({6-amino-5-[5-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate

In a manner similar to that described in Example 53,6-amino-5-(5-(3-(2-fluoro-5-methylphenyl)ureido)benzo[b]thiophen-2-yl)nicotinicacid and (S)-methyl 5-(S-methylsulfonimidoyl)pentanoate were convertedto the title compound.

¹H NMR (DMSO-d₆) δ: 9.19 (s, 1H), 8.61 (d, J=2.1 Hz, 1H), 8.51 (d, J=2.3Hz, 1H), 8.12 (d, J=1.8 Hz, 1H), 8.00-8.05 (m, 2H), 7.88 (d, J=8.5 Hz,1H), 7.60 (s, 1H), 7.36 (dd, J=8.8, 2.1 Hz, 1H), 7.11 (dd, J=11.4, 8.2Hz, 1H), 6.77-6.84 (m, 1H), 6.76 (s, 2H), 3.53-3.65 (m, 5H), 3.41 (s,3H), 2.40 (t, J=7.0 Hz, 2H), 2.28 (s, 3H), 1.75-1.88 (m, 2H), 1.64-1.74(m, 2H)

Example 55

methyl5-[N-({6-amino-5-[5-({[(3-chloro-4-fluorophenyl)amino]carbonyl}amino)-1-benzothien-2-yl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate

In a manner similar to that described in Example 53,6-amino-5-(5-(3-(3-chloro-4-fluorophenyl)ureido)benzo[b]thiophen-2-yl)nicotinicacid and (S)-methyl 5-(S-methylsulfonimidoyl)pentanoate were convertedto the title compound.

¹H NMR (DMSO-d₆) δ: 8.90 (s, 1H), 8.90 (s, 1H), 8.61 (d, J=2.3 Hz, 1H),8.08 (d, J=2.1 Hz, 1H), 8.01 (d, J=2.3 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H),7.81-7.86 (m, 1H), 7.60 (s, 1H), 7.31-7.41 (m, 3H), 6.76 (s, 2H),3.54-3.63 (m, 5H), 3.41 (s, 3H), 2.39 (t, J=7.2 Hz, 2H), 1.75-1.88 (m,2H), 1.63-1.74 (m, 2H)

Preparation 7

S(CH₂CH₂CH₂OTBDMS)₂

2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8-thia-3,13-disilapentadecane

To the solution of 3,3′-thiodipropanol (5 g, 32.6 mmol, 1 eq) andtert-butyldimethylsilyl chloride (13.18 g, 2.6 eq) in anhydrous DMF (25mL) at 0° C. was added imidazole (11.21 g, 5 eq). After the reaction wasstirred at room temperature for one hour, it was partitioned betweenethyl acetate and water. The organic layer was isolated, washed oncemore with water, then brine, and lastly dried with anhydrous sodiumsulfate. The upper clear solution was decanted, concentrated, and theoily residue was subject to a column chromatography (EtOC-Hex: from 1:9to 4:1).2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8-thia-3,13-disilapentadecane,was obtained as clear oil in 12.32 g.

¹H NMR (DMSO-d₆) δ: 3.64 (t, J=6.2 Hz, 4H), 2.49-2.53 (m, 4H), 1.65-1.71(m, 4H), 0.86 (s, 18H), 0.03 (s, 12H)

Preparation 8

O═S(CH₂CH₂CH₂OTBDMS)₂

2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8-thia-3,13-disilapentadecane8-oxide

A solution of sodium (meta)periodate (7.751 g, 1.1 eq) in water (40 mL)was slowly poured into a solution of2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8-thia-3,13-disilapentadecane,(12.32 g, 1 eq) in methanol (150 mL) at 0° C. and the reaction mixturewas stirred at room temperature for 2 hours. The reaction mixture wasthen filtered through a pad of celite and silica gel which was washedwith methanol. The filtrate was concentrated under reduced pressure at atemperature below 25° C. The residue was diluted with brine andextracted a couple of times with chloroform. All organic solvents werecombined, dried with anhydrous sodium sulfate, and concentrated to givea clear oil as crude2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8-thia-3,13-disilapentadecane8-oxide, in amount of 12.84 g.

¹H NMR (DMSO-d₆) δ: 3.69 (t, J=6.2 Hz, 4H), 2.59-2.83 (m, 4H), 1.80(tdd, J=6.8, 6.7, 6.4 Hz, 4H), 0.86 (s, 18H), 0.04 (s, 12H)

Preparation 9

8-imino-2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8λ⁴-thia-3,13-disilapentadecane8-oxide

To the solution of above obtained crude oil2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8-thia-3,13-disilapentadecane8-oxide, in anhydrous dichloromethane (150 mL) was addedtrifluoroacetamide (7.60 g, 2 eq), magnesium oxide (5.256 g. 4 eq),rhodium acetate dimer (432 mg, 0.03 eq), and (diacetoxyiodo)benzene(15.75 g, 1.5 eq) under nitrogen atmosphere at room temperature. Thegreenish reaction mixture was stirred at room temperature for 18 hours.Then additional amount of trifluoroacetamide (3.0 g), rhodium acetatedimer (300 mg), (diacetoxyiodo)benzene (5.0 g), and anhydrousdichloromethane (100 mL) was added. The mixture was continued beingstirred at room temperature for another 3 hours and then filteredthrough a pad of celite and silica gel. The pad was washed first withdichloromethane followed by MeOH-DCM (1:5). The filtrate wasconcentrated and the brown oil was taken up into methanol (200 mL).Potassium carbonate (22.53 g, 5 eq) was added to the newly formedsolution. After the mixture was stirred at room temp for 2 hours, it wasfiltered through a pad of celite and silica gel. The pad was washedfirst with DCM-EtOAC (1:1) followed by a later 10% (v/v) addition ofMeOH with stirring of the sediment on top of the pad. The filtrate wasconcentrated and the residue mixture was treated with DCM-EtOAc (2:3)with stirring at room temp for 30 minutes. The mixture was filteredagain through a pad of celite and silica gel. This filtration andconcentration circle may be repeated a couple of times such that most ofthe solid by-product was removed and a redish oil was obtained. Upon agradient column chromatography (EtOAc-HEX 1:20 to 1:1)8-imino-2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8λ⁴-thia-3,13-disilapentadecane8-oxide, was obtained as a reddish oil in amount of 9.538 g with a totalyield of 72% for 4 steps.

¹H NMR (DMSO-d₆) δ: 3.67 (t, J=6.3 Hz, 4H), 3.65 (s, 1H), 2.99 (t, J=7.9Hz, 4H), 1.82-1.88 (m, 4H), 0.86 (s, 18H), 0.04 (s, 12H)

Example 56

6-amino-N-[bis(3-hydroxypropyl)(oxido)-λ⁴-sulfanylidene]-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinamide

The reaction mixture of8-imino-2,2,3,3,13,13,14,14-octamethyl-4,12-dioxa-8λ⁴-thia-3,13-disilapentadecane8-oxide, (102.25 mg, 0.25 mmol, 1 eq),6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinicacid (89 mg, 1 eq), DMAP (6.125 mg, 0.2 eq), and EDCI (57.6 mg, 1.2 eq)in anhydrous DCE (2.5 mL) was heated at 70° C. for 2 hours. It was thendiluted with DCM, washed sequentially with aqueous NH₄Cl, saturatedaqueous NaHCO₃, and brine, and dried with anhydrous sodium sulfate. Theupper clear solution was decanted, concentrated, and the oily residuewas subject to gradient column chromatography (EtOAc-Hex 1:30 to 2:1)yielding6-amino-N-[bis(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)(oxido)-λ⁴-sulfanylidene]-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinamideas a white foam in amount of 70 mg.

¹H NMR (DMSO-d₆) δ: 8.77 (s, 1H), 8.59-8.61 (m, 2H), 8.10 (d, J=2.1 Hz,1H), 8.01 (d, J=2.1 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.57 (s, 1H), 7.37(dd, J=8.8, 2.1 Hz, 1H), 7.33 (s, 1H), 7.25 (d, J=8.2 Hz, 1H), 7.16 (t,J=7.8 Hz, 1H), 6.80 (d, J=7.6 Hz, 1H), 6.76 (br. s., 2H), 3.71 (t, J=6.2Hz, 4H), 3.62-3.70 (m, 4H), 2.29 (s, 3H), 1.89-1.98 (m, 4H), 0.85 (s,18H), 0.03 (s, 12H)

To the solution of6-amino-N-[bis(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)(oxido)-λ⁴-sulfanylidene]-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinamide(70 mg, 0.086 mmol, 1 eq) in anhydrous THF (2 mL) at 0° C. was addeddropwise tetrabutylammonium fluoride (0.355 mL, 1.0 M in anhyd. THF, 4.1eq) and the reaction was stirred at that temp for 2 hours. The reactionwas then partitioned between saturated aqueous NaHCO₃ and ethyl acetate.The organic layer was further washed with aqueous NH₄Cl, brine, lastlydried with anhydrous Na₂SO₄. The upper solution was decanted,concentrated, and the solid residue was wrapped with silica gel whichwas subject to a gradient column chromatography (EtOAc-Hex 6:1 toMeOH-EtOAc 1:9) to give6-amino-N-[bis(3-hydroxypropyl)(oxido)-λ⁴-sulfanylidene]-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinamideas a slightly brown solid in amount of 42 mg.

¹H NMR (DMSO-d₆) δ: 8.84 (s, 1H), 8.67 (s, 1H), 8.62 (d, J=2.3 Hz, 1H),8.10 (d, J=1.8 Hz, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H),7.59 (s, 1H), 7.37 (dd, J=8.5, 2.1 Hz, 1H), 7.33 (s, 1H), 7.25 (d, J=8.2Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 6.79 (d, J=7.3 Hz, 1H), 6.76 (s, 2H),4.74 (t, J=5.3 Hz, 2H), 3.62-3.68 (m, 2H), 3.55-3.60 (m, 2H), 3.52 (q,J=6.1 Hz, 4H), 2.29 (s, 3H), 1.84-1.96 (m, 4H)

Example 57

N-[dimethyl(oxido)-λ⁴-sulfanylidene]-5-{5-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]-1-benzothien-2-yl}nicotinamide

Synthesized using a procedure similar to Example 1.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 9.35 (s, 1H) 9.18 (d, J=2.35 Hz, 1H)9.09 (d, J=2.05 Hz, 1H) 8.94 (d, J=2.93 Hz, 1H) 8.66 (dd, J=7.19, 2.20Hz, 1H) 8.51 (t, J=2.05 Hz, 1H) 8.19 (d, J=1.76 Hz, 1H) 8.08 (s, 1H)7.96 (d, J=8.80 Hz, 1H) 7.51 (dd, J=10.56, 8.80 Hz, 1H) 7.38-7.42 (m,2H) 3.54 (s, 6H)

Example 58

5-{5-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]-1-benzothien-2-yl}-N-[dimethyl(oxido)-Δ⁴-sulfanylidene]nicotinamide

Synthesized using a procedure similar to Example 1.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 9.22 (s, 1H) 9.18 (d, J=2.35 Hz, 1H)9.08 (d, J=1.76 Hz, 1H) 9.03 (s, 1H) 8.51 (t, J=2.20 Hz, 1H) 8.15 (dd,J=4.70, 2.35 Hz, 2H) 8.07 (s, 1H) 7.94 (d, J=8.51 Hz, 1H) 7.65-7.68 (m,1H) 7.61-7.64 (m, 1H) 7.42 (dd, J=8.51, 2.05 Hz, 1H) 3.54 (s, 6H)

The compounds represented by Formula II can be synthesized according tothe following example.

Example 60

6-amino-N-[dimethyl(oxido)-λ⁴-sulfanylidene]-5-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]nicotinamide

1-(2-fluoro-5-methylphenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea(212 mg, 0.6 mmoles) and6-amino-N-[dimethyl(oxido)-λ⁴-sulfanylidene]-5-iodonicotinamide (170 mg,0.5 mmoles) was added to a mixture of 6 ml of dioxane and 2 ml of 2Maqueous Sodium Carbonate. Next, Palladium(II) Acetate (˜5 mol %, 6 mg)and Triphenylphosphene (˜20 mol %, 27 mg) was added, followed by 2 ml ofdioxane. Dry nitrogen was bubbled through the resulting solution for 15minutes. Following this, the reaction mixture was set up with a refluxcondenser, under nitrogen atmosphere, and heated at 95 C for 2 hours.The reaction was then cooled to room temperature and 40 ml of ethylacetate was added. The mixture was transferred to a separatory funneland extracted with saturated Sodium Bicarbonate (3×40 ml) followed bysaturated NaCl (3×40 ml). The organic layer was dried with anhydrousSodium Sulfate, loaded onto silica and columned using ethylacetate/hexanes, to give 120 mg of the product.

¹H NMR (dmso) δ: 9.18 (s, 1H), 8.55 (d, J=2.0 Hz, 1H), 8.50 (d, J=2.6Hz, 1H), 8.00 (dd, J=7.8, 1.9 Hz, 1H), 7.75 (d, J=2.3 Hz, 1H), 7.52-7.59(m, 2H), 7.30-7.38 (m, 2H), 7.10 (dd, J=11.4, 8.2 Hz, 1H), 6.79 (s, 1H),6.24 (s, 2H), 3.41 (s, 6H), 2.27 (s, 3H)

Example 64

dimethyl(6-amino-5-(4-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)pyridin-3-yl)phosphonate

The reaction mixture of dimethyl(6-amino-5-(4-aminophenyl)pyridin-3-yl)phosphonate (30 mg, 0.10 mmol, 1eq) and 1-isocyanato-3-(trifluoromethyl)benzene (0.018 mL, 1.2 eq) inanhydrous DMF (0.5 mL) under anhydrous nitrogen atmosphere was stirredat room temperature for an hour. It was then diluted with ethyl acetate,washed sequentially with aqueous ammonium chloride, saturated aqueoussodium bicarbonate, brine, and lastly dried with anhydrous sodiumsulfate. The upper clear solution was decanted, concentrated, and thesolid residue was subject to a gradient column chromatography (EtOAc-Hex2:1 to MeOH-EtOAc 1:20) to yield dimethyl(6-amino-5-(4-(3-(3-(trifluoromethyl)phenyl)ureido)phenyl)pyridin-3-yl)phosphonate as a white solid in amount of 41 mg.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 9.12 (s, 1H) 9.01 (s, 1H) 8.19 (dd,J=6.37, 2.12 Hz, 1H) 8.03 (s, 1H) 7.56-7.64 (m, 3H) 7.49-7.55 (m, 1H)7.29-7.42 (m, 4H) 6.44 (br. s., 2H) 3.65 (s, 3H) 3.62 (s, 3H).

Example 65

diethyl[6-amino-5-(4-{[(2-fluoro-5-methylphenyl)carbamoyl]amino}phenyl)pyridin-3-yl]phosphonate

Synthesized using a procedure similar to Example 64.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 9.22 (s, 1H) 8.51 (d, J=2.49 Hz, 1H)8.19 (dd, J=6.37, 2.12 Hz, 1H) 8.00 (dd, J=7.84, 1.83 Hz, 1H) 7.57 (d,J=8.64 Hz, 2H) 7.33-7.42 (m, 3H) 7.11 (dd, J=11.28, 8.35 Hz, 1H)6.77-6.85 (m, 1H) 6.40 (br. s., 2H) 3.93-4.05 (m, 4H) 2.28 (s, 3H) 1.23(t, J=7.03 Hz, 6H)

Example 66

dimethyl{6-amino-5-[4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyridin-3-yl}phosphonate

Synthesized using a procedure similar to Example 64.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 9.36 (br. s., 1H) 8.95 (br. s., 1H) 8.63(dd, J=7.33, 2.20 Hz, 1H) 8.19 (dd, J=6.37, 2.12 Hz, 1H) 7.55-7.61 (m,2H) 7.51 (dd, J=10.99, 8.94 Hz, 1H) 7.36-7.44 (m, 4H) 6.45 (br. s., 2H)3.66 (s, 3H) 3.62 (s, 3H)

Example 67

dimethyl[6-amino-5-(4-{[(2-fluoro-5-methylphenyl)carbamoyl]amino}phenyl)pyridin-3-yl]phosphonate

Synthesized using a procedure similar to Example 64.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 9.23 (s, 1H) 8.53 (d, J=1.90 Hz, 1H)8.19 (dd, J=6.30, 2.05 Hz, 1H) 7.97-8.02 (m, 1H) 7.56 (d, J=8.50 Hz, 2H)7.34-7.42 (m, 3H) 7.11 (dd, J=11.28, 8.50 Hz, 1H) 6.77-6.84 (m, 1H) 6.44(br. s., 2H) 3.65 (s, 3H) 3.62 (s, 3H) 2.28 (s, 3H)

Example 63

1-{4-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]phenyl}-3-phenylurea

Synthesized using a procedure similar to Example 62.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 8.81 (br. s., 1H) 8.71 (br. s., 1H) 8.18(d, J=1.76 Hz, 1H) 7.91-7.97 (m, 1H) 7.53-7.57 (m, 2H) 7.47 (d, J=7.92Hz, 2H) 7.32-7.37 (m, 2H) 7.26-7.31 (m, 2H) 6.97 (t, J=7.34 Hz, 1H) 5.98(br. s., 2H) 1.27 (s, 12H)

Example 59

6-amino-N-[dimethyl(oxido)-λ⁴-sulfanylidene]-5-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]nicotinamide

Synthesized using a procedure similar to Example 69.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 9.22 (s, 1H) 8.56 (d, J=2.20 Hz, 1H)8.53 (d, J=2.05 Hz, 1H) 8.00 (dd, J=7.78, 1.61 Hz, 1H) 7.74 (d, J=2.05Hz, 1H) 7.56 (d, J=8.51 Hz, 2H) 7.36 (d, J=8.51 Hz, 2H) 7.11 (dd,J=11.30, 8.36 Hz, 1H) 6.79-6.83 (m, 1H) 6.24 (br. s., 2H) 4.73 (t,J=5.36 Hz, 2H) 3.54-3.66 (m, 4H) 3.51 (q, J=6.02 Hz, 4H) 2.28 (s, 3H)1.83-1.95 (m, 4H)

Example 70

dimethyl5,5′-(N-{[6-amino-5-(4-{[(3-methylphenyl)carbamoyl]amino}phenyl)pyridin-3-yl]carbonyl}sulfonimidoyl)dipentanoate

Synthesized using a procedure similar to Example 69.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 8.79 (s, 1H) 8.61 (s, 1H) 8.55 (d,J=2.20 Hz, 1H) 7.73 (d, J=2.05 Hz, 1H) 7.56 (d, J=8.66 Hz, 2H) 7.34 (d,J=8.51 Hz, 2H) 7.31 (s, 1H) 7.24 (d, J=8.36 Hz, 1H) 7.16 (t, J=7.78 Hz,1H) 6.80 (d, J=7.34 Hz, 1H) 6.23 (br. s., 2H) 3.49-3.63 (m, 10H) 2.38(t, J=7.26 Hz, 4H) 2.28 (s, 3H) 1.62-1.85 (m, 8H)

Example 71

dimethyl5,5′-(N-{[6-amino-5-(4-{[(2-fluoro-5-methylphenyl)carbamoyl]amino}phenyl)pyridin-3-yl]carbonyl}sulfonimidoyl)dipentanoate

Synthesized using a procedure similar to Example 69.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 9.19 (s, 1H) 8.55 (d, J=2.20 Hz, 1H)8.50 (d, J=2.35 Hz, 1H) 8.00 (dd, J=7.92, 1.76 Hz, 1H) 7.74 (d, J=2.05Hz, 1H) 7.56 (d, J=8.66 Hz, 2H) 7.35 (d, J=8.51 Hz, 2H) 7.11 (dd,J=11.30, 8.36 Hz, 1H) 6.79-6.83 (m, 1H) 6.24 (br. s., 2H) 3.50-3.62 (m,10H) 2.38 (t, J=7.26 Hz, 4H) 2.28 (s, 3H) 1.63-1.84 (m, 8H)

Example 72

dimethyl5,5′-[N-({6-amino-5-[4-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyridin-3-yl}carbonyl)sulfonimidoyl]dipentanoate

Synthesized using a procedure similar to Example 69.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 9.08 (s, 1H) 8.95 (s, 1H) 8.55 (d,J=2.20 Hz, 1H) 8.03 (s, 1H) 7.74 (d, J=2.20 Hz, 1H) 7.56-7.61 (m, 3H)7.52 (t, J=8.00 Hz, 1H) 7.36 (d, J=8.51 Hz, 2H) 7.32 (d, J=7.63 Hz, 1H)6.24 (br. s., 2H) 3.50-3.62 (m, 10H) 2.38 (t, J=7.34 Hz, 4H) 1.72-1.84(m, 4H) 1.64-1.70 (m, 4H)

Example 68

dimethyl(6-amino-5-{4-[(phenylcarbamoyl)amino]phenyl}pyridin-3-yl)phosphonate

Synthesized using a procedure similar to Example 64.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.85 (s, 1H) 8.71 (s, 1H) 8.19 (dd,J=6.37, 2.12 Hz, 1H) 7.54-7.60 (m, 2H) 7.44-7.49 (m, 2H) 7.33-7.41 (m,3H) 7.29 (t, J=7.91 Hz, 2H) 6.94-7.01 (m, 1H) 6.43 (br. s., 2H) 3.65 (s,3H) 3.62 (s, 3H)

Example 62

1-(4-(2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea

To the nitrogen bubbled mixture of1-(4-(2-amino-5-bromopyridin-3-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea(487 mg, 1.17 mmol, 1 eq), bis(pinacolato)diboron (0.36 g, 1.2 eq), andpotassium acetate (0.46 g, 4 eq) in anhydrous 1,4-dioxane (6 mL) wasadded [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (1:1) (0.14 g, 0.15 eq) and the mixture washeated at 120° C. for one and half hours. After the reaction was cooledto room temperature, it was filtered through a celite pad and washedwith ethyl acetate. The filtrate was collected, washed sequentially withaqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine,and lastly dried with anhydrous sodium sulfate. The upper clear solutionwas decanted, concentrated, and the brown oily residue was subject to agradient column chromatography (EtOAc-Hex 1:4 to 4:1) to yield1-(4-(2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)phenyl)-3-(2-fluoro-5-methylphenyl)ureaas a brown oil which solidified in vacuo in amount of 101 mg.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 9.17 (s, 1H) 8.49 (br. s., 1H) 8.18 (d,J=1.76 Hz, 1H) 8.00 (d, J=7.92 Hz, 1H) 7.51-7.57 (m, 2H) 7.42 (d, J=1.76Hz, 1H) 7.33-7.37 (m, 2H) 7.11 (dd, J=11.30, 8.36 Hz, 1H) 6.78-6.84 (m,1H) 5.99 (s, 2H) 2.28 (s, 3H) 1.27 (s, 12H).

Example 61

(6-amino-5-(4-(3-(2-fluoro-5-methylphenyl)ureido)phenyl)pyridin-3-yl)boronicacid

To the solution of1-(4-(2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)phenyl)-3-(2-fluoro-5-methylphenyl)urea(AGN-227971, 108 mg, 0.234 mmol, 1 eq) in anhydrous tetrahydrofuran (2mL) was added aq HCl (3 N, 2 mL) and the reaction was first stirred atroom temperature for two hours. Additional conc. HCl (0.5 mL) wasdropwise added to the reaction and the mixture was stirred at 50° C. forfurther four hours. The reaction was then poured into saturated aqueoussodium bicarbonate and extracted with ethyl acetate. The organic layerwas isolated, washed with brine, and dried with anhydrous sodiumsulfate. The upper clear solution was decanted, concentrated to lesseramount, and the solid crashed-out was filtered. This solid was furtherpurified by a reversed phase chromatography (from WATER-CH₃CN 9:1 toCH₃CN) to give(6-amino-5-(4-(3-(2-fluoro-5-methylphenyl)ureido)phenyl)pyridin-3-yl)boronicacid as a grey solid in amount of 7 mg.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 9.15 (s, 1H) 8.48 (d, J=2.49 Hz, 1H)8.31 (d, J=1.76 Hz, 1H) 8.00 (dd, J=7.85, 1.83 Hz, 1H) 7.80 (s, 2H) 7.68(d, J=1.91 Hz, 1H) 7.52-7.56 (m, 2H) 7.34-7.38 (m, 2H) 7.11 (dd,J=11.30, 8.36 Hz, 1H) 6.78-6.83 (m, 1H) 5.71 (s, 2H) 2.28 (s, 3H)

Example 69

6-amino-N-[bis(3-hydroxypropyl)(oxido)-λ⁴-sulfanylidene]-5-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]nicotinamide

To the solution of6-amino-5-(4-aminophenyl)-N-[bis(3-hydroxypropyl)(oxido)-λ⁴-sulfanylidene]nicotinamide(39 mg, 0.1 mmol, 1.0 eq) in anhydrous THF (1 mL) was added1-isocyanato-3-methylbenzene (0.013 mL, 1.0 eq) dropwise. The reactionwas stirred at room temperature for 1 hour and then diluted with EtOAc.The organic layer was washed sequentially with saturated aq NaHCO₃, aqNH₄Cl, brine, and finally dried with anhydrous Na₂SO₄. The supernatantliquid was decanted, concentrated, and the oily residue was subject to agradient column chromatography (EtOAc-Hex 7:1 to MeOH-EtOAc 1:9)yielding6-amino-N-[bis(3-hydroxypropyl)(oxido)-λ⁴-sulfanylidene]-5-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenyl]nicotinamideas a white solid in amount of 30 mg.

¹H NMR (600 MHz, DMSO-d₆) δ ppm 8.82 (br. s., 1H) 8.64 (br. s., 1H) 8.56(d, J=2.05 Hz, 1H) 7.74 (d, J=2.05 Hz, 1H) 7.56 (d, J=8.51 Hz, 2H) 7.34(d, J=8.22 Hz, 2H) 7.31 (s, 1H) 7.24 (d, J=7.63 Hz, 1H) 7.16 (t, J=7.78Hz, 1H) 6.80 (d, J=7.34 Hz, 1H) 6.23 (br. s., 2H) 4.72 (t, J=5.28 Hz,2H) 3.49-3.66 (m, 8H) 2.28 (s, 3H) 1.82-1.95 (m, 4H)

Example 74

methyl6-amino-5-[4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyridine-3-carboxylate

To methyl 6-amino-5-(4-aminophenyl)nicotinate (0.18 mmoles) in 3 ml oftetrahydrofuran (THF) under nitrogen atmosphere was added a solution of1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene (0.22 mmoles, 1.2equivalents) in 1 ml THF. The reaction was stirred at room temperatureunder nitrogen atmosphere for 30 minutes. Following this, the reactionwas loaded onto silica and columned using ethyl acetate-hexanes, to give25 mg of the product.

¹H NMR (dmso-d⁶) δ: 9.29-9.34 (m, 1H), 8.92 (br. s., 1H), 8.60-8.65 (m,1H), 8.51 (d, J=2.4 Hz, 1H), 7.68 (d, J=2.2 Hz, 1H), 7.57 (d, J=8.6 Hz,2H), 7.46-7.52 (m, 1H), 7.38 (d, J=8.6 Hz, 3H), 6.52 (br. s., 2H), 3.78(s, 3H)

Example 75

methyl6-amino-5-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyridine-3-carboxylate

Synthesized using a procedure similar to methyl6-amino-5-[4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyridine-3-carboxylate.

¹H NMR (dmso-d6) δ: 9.20-9.25 (m, 1H), 9.04 (s, 1H), 8.50 (d, J=2.2 Hz,1H), 8.11 (d, J=2.4 Hz, 1H), 7.59-7.68 (m, 3H), 7.57 (d, J=8.6 Hz, 2H),7.37 (d, J=8.6 Hz, 2H), 6.51 (br. s., 2H), 3.77 (s, 3H)

Example 73

methyl6-amino-5-(4-{[(2-fluoro-5-methylphenyl)carbamoyl]amino}phenyl)pyridine-3-carboxylate

Synthesized using a procedure similar to methyl6-amino-5-[4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyridine-3-carboxylate.

¹H NMR (dmso-d⁶) δ: 9.21 (s, 1H), 8.50 (d, J=2.2 Hz, 2H), 7.97-8.01 (m,1H), 7.67 (d, J=2.2 Hz, 1H), 7.54-7.57 (m, 2H), 7.36 (d, J=8.6 Hz, 2H),7.10 (dd, J=11.5, 8.3 Hz, 1H), 6.77-6.82 (m, 1H), 6.51 (br. s., 2H),3.78 (s, 3H), 2.27 (s, 3H).

Example 76

methyl6-amino-5-{4-[(phenylcarbamoyl)amino]phenyl}pyridine-3-carboxylate

Synthesized using a procedure similar to methyl6-amino-5-[4-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}amino)phenyl]pyridine-3-carboxylate.

¹H NMR (dmso-d⁶) δ: 8.81 (s, 1H), 8.68 (s, 1H), 8.50 (d, J=2.2 Hz, 1H),7.66-7.68 (m, 1H), 7.54-7.57 (m, J=8.6 Hz, 2H), 7.46 (dd, J=8.6, 1.0 Hz,2H), 7.35 (d, J=8.6 Hz, 2H), 7.28 (t, J=7.9 Hz, 2H), 6.97 (t, J=7.4 Hz,1H), 6.51 (br. s., 2H), 3.77 (s, 3H).

Biological data for the compounds of the present invention was generatedby use of the following assays.

VEGFR2 Kinase Assay

Biochemical KDR kinase assays were performed in 96 well microtiterplates that were coated overnight with 75 μg/well of poly-Glu-Tyr (4:1)in 10 mM Phosphate Buffered Saline (PBS), pH 7.4. The coated plates werewashed with 2 mls per well PBS+0.05% Tween-20 (PBS-T), blocked byincubation with PBS containing 1% BSA, then washed with 2 mls per wellPBS-T prior to starting the reaction. Reactions were carried out in 100μL reaction volumes containing 2.7 μM ATP in kinase buffer (50 mM Hepesbuffer pH 7.4, 20 mM MgCl₂, 0.1 mM MnCl₂ and 0.2 mM Na₃VO₄). Testcompounds were reconstituted in 100% DMSO and added to the reaction togive a final DMSO concentration of 5%. Reactions were initiated by theaddition 20 ul per well of kinase buffer containing 200-300 ng purifiedcytoplasmic domain KDR protein (BPS Bioscience, San Diego, Calif.).Following a 15 minute incubation at 30° C., the reactions were washed 2mls per well PBS-T. 100 μl of a monoclonal anti-phosphotyrosineantibody-peroxidase conjugate diluted 1:10,000 in PBS-T was added to thewells for 30 minutes. Following a 2 mls per well wash with PBS-Tween-20,100 μl of O-Phenylenediamine Dihydrochloride in phosphate-citratebuffer, containing urea hydrogen peroxide, was added to the wells for7-10 minutes as a colorimetric substrate for the peroxidase. Thereaction was terminated by the addition of 100 μl of 2.5N H₂SO₄ to eachwell and read using a microplate ELISA reader set at 492 nm. IC₅₀ valuesfor compound inhibition were calculated directly from graphs of opticaldensity (arbitrary units) versus compound concentration followingsubtraction of blank values.

VEGFR2 Cellular Assay

Automated FLIPR (Fluorometric Imaging Plate Reader) technology was usedto screen for inhibitors of VEGF induced increases in intracellularcalcium levels in fluorescent dye loaded endothelial cells. HUVEC (humanumbilical vein endothelial cells) (Clonetics) were seeded in 384-wellfibronectin coated black-walled plates overnight @ 37° C./5% CO2. Cellswere loaded with calcium indicator Fluo-4 for 45 minutes at 37° C. Cellswere washed 2 times (Elx405, Biotek Instruments) to remove extracellulardye. For screening, cells were pre-incubated with test agents for 30minutes, at a single concentration (10 uM) or at concentrations rangingfrom 0.0001 to 10.0 uM followed by VEGF₁₆₅ stimulation (10 ng/mL).Changes in fluorescence at 516 nm were measured simultaneously in all384 wells using a cooled CCD camera. Data were generated by determiningmax-min fluorescence levels for unstimulated, stimulated, and drugtreated samples. IC₅₀ values for test compounds were calculated from %inhibition of VEGF stimulated responses in the absence of inhibitor.

PDGFRβ Kinase Assay

Biochemical PDGFRβ kinase assays were performed in 96 well microtiterplates that were coated overnight with 75 μg of poly-Glu-Tyr (4:1) in 10mM Phosphate Buffered Saline (PBS), pH 7.4. The coated plates werewashed with 2 mls per well PBS+0.05% Tween-20 (PBS-T), blocked byincubation with PBS containing 1% BSA, then washed with 2 mls per wellPBS-T prior to starting the reaction. Reactions were carried out in 100μL reaction volumes containing 36 μM ATP in kinase buffer (50 mM Hepesbuffer pH 7.4, 20 mM MgCl₂, 0.1 mM MnCl₂ and 0.2 mM Na₃VO₄). Testcompounds were reconstituted in 100% DMSO and added to the reaction togive a final DMSO concentration of 5%. Reactions were initiated by theaddition 20 μl per well of kinase buffer containing 200-300 ng purifiedcytoplasmic domain PDGFR-b protein (Millipore). Following a 60 minuteincubation at 30° C., the reactions were washed 2 mls per well PBS-T.100 μl of a monoclonal anti-phosphotyrosine antibody-peroxidaseconjugate diluted 1:10,000 in PBS-T was added to the wells for 30minutes. Following a 2 mls per well wash with PBS-Tween-20, 100 μl ofO-Phenylenediamine Dihydrochloride in phosphate-citrate buffer,containing urea hydrogen peroxide, was added to the wells for 7-10minutes as a colorimetric substrate for the peroxidase. The reaction wasterminated by the addition of 100 μl of 2.5N H₂SO₄ to each well and readusing a microplate ELISA reader set at 492 nm. IC₅₀ values for compoundinhibition were calculated directly from graphs of optical density(arbitrary units) versus compound concentration following subtraction ofblank values.

PDGFRβ Cellular Assay

Automated FLIPR (Fluorometric Imaging Plate Reader) technology was usedto screen for inhibitors of PDGF-induced increases in intracellularcalcium levels in fluorescent dye loaded endothelial cells. NHDF-Ad(Normal Human Dermal Fibroblasts, Adult; Lonza) were seeded in 384-wellfibronectin coated black-walled plates overnight @ 37° C./5% CO2. Cellswere loaded with calcium indicator Fluo-4 for 45 minutes at 37° C. Cellswere washed 2 times (Elx405, Biotek Instruments) to remove extracellulardye. For screening, cells were pre-incubated with test agents for 30minutes, at a single concentration (10 uM) or at concentrations rangingfrom 0.0001 to 10.0 uM followed by PDGF-BB stimulation (30 ng/mL).Changes in fluorescence at 516 nm were measured simultaneously in all384 wells using a cooled CCD camera. Data were generated by determiningmax-min fluorescence levels for unstimulated, stimulated, and drugtreated samples. IC₅₀ values for test compounds were calculated from %inhibition of PDGF-BB stimulated responses in the absence of inhibitor.

PKR KinaseGlo Assay

Commercially available recombinant human GST-PKR (SignalChem, Canada;1.5 uM-2 uM stock) is diluted to 500 nM in assay buffer (20 mM Tris-HCl,pH 7.2, 10 mM KCl, 10 mM MgCl2, 10% glycerol). Preactivated PKR isdispensed to 384/96-well black plates at 3.125/12.5 uls/well using theliquid handler Janus. Appropriate dilutions of inhibitors are added to384/96-well plate followed by 6.6 uM ATP (final) and incubated for 10minutes at room temperature. The remaining ATP/well is determined byadding 6.25/25 uls/well Kinase-Glo assay mix (Promega) and luminescenceis measured on EnVision luminescence plate reader (integration time, 0.2sec; Perkin-Elmer, Massachusetts, USA). The % inhibition for thecompounds is calculated using ATP only (100% inhibition) and PKR+ATP (0%inhibition). IC50 values are determined by plotting % activity versusinhibitor concentration. Curves are fitted using Activity base XLfit(IDBS, UK) using the formula—4 Parameter Logistic Modelfit=(A+((B−A)/(1+(10^((C−x)*D)))))inv=(C−(log(((B−A)/(y−A))−1)/D))res=(y−fit)

The biological results for the various compounds are shown in Tables 2,3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 below.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18^(th) Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compounds of this invention may also be delivered orally,subcutaneously, intravenously, intrathecally or some suitablecombination(s) thereof.

In addition to the common dosage forms set out above, the compounds ofthis invention may also be administered by controlled release meansand/or delivery devices such as those described in U.S. Pat. Nos.3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,719; and5,366,738.

For use where a composition for intravenous administration is employed,a suitable daily dosage range for anti-inflammatory,anti-atherosclerotic or anti-allergic use is from about 0.001 mg toabout 25 mg (preferably from 0.01 mg to about 1 mg) of a compound ofthis invention per kg of body weight per day and for cytoprotective usefrom about 0.1 mg to about 100 mg (preferably from about 1 mg to about100 mg and more preferably from about 1 mg to about 10 mg) of a compoundof this invention per kg of body weight per day. For the treatment ofdiseases of the eye, ophthalmic preparations for ocular administrationcomprising 0.001-1% by weight solutions or suspensions of the compoundsof this invention in an acceptable ophthalmic formulation may be used.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The magnitude of prophylactic or therapeutic dose of a compound of thisinvention will, of course, vary with the nature of the severity of thecondition to be treated and with the particular compound and its routeof administration. It will also vary according to the age, weight andresponse of the individual patient. It is understood that a specificdaily dosage amount can simultaneously be both a therapeuticallyeffective amount, e.g., for treatment to slow progression of an existingcondition, and a prophylactically effective amount, e.g., for preventionof condition.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 0.001 mg to about 500 mg. In oneembodiment, the quantity of active compound in a unit dose ofpreparation is from about 0.01 mg to about 250 mg. In anotherembodiment, the quantity of active compound in a unit dose ofpreparation is from about 0.1 mg to about 100 mg. In another embodiment,the quantity of active compound in a unit dose of preparation is fromabout 1.0 mg to about 100 mg. In another embodiment, the quantity ofactive compound in a unit dose of preparation is from about 1.0 mg toabout 50 mg. In still another embodiment, the quantity of activecompound in a unit dose of preparation is from about 1.0 mg to about 25mg.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 0.01mg/day to about 2000 mg/day of the compounds of the present invention.In one embodiment, a daily dosage regimen for oral administration isfrom about 1 mg/day to 1000 mg/day. In another embodiment, a dailydosage regimen for oral administration is from about 1 mg/day to 500mg/day. In another embodiment, a daily dosage regimen for oraladministration is from about 100 mg/day to 500 mg/day. In anotherembodiment, a daily dosage regimen for oral administration is from about1 mg/day to 250 mg/day. In another embodiment, a daily dosage regimenfor oral administration is from about 100 mg/day to 250 mg/day. In stillanother embodiment, a daily dosage regimen for oral administration isfrom about 1 mg/day to 100 mg/day. In still another embodiment, a dailydosage regimen for oral administration is from about 50 mg/day to 100mg/day. In a further embodiment, a daily dosage regimen for oraladministration is from about 1 mg/day to 50 mg/day. In anotherembodiment, a daily dosage regimen for oral administration is from about25 mg/day to 50 mg/day. In a further embodiment, a daily dosage regimenfor oral administration is from about 1 mg/day to 25 mg/day. The dailydosage may be administered in a single dosage or can be divided intofrom two to four divided doses.

In one aspect, the present invention provides a kit comprising atherapeutically effective amount of at least one compound of the presentinvention, or a pharmaceutically acceptable salt of said compound and apharmaceutically acceptable carrier, vehicle or diluents, and directionsfor the use of said kit.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in therelevant art and are intended to fall within the scope of the appendedclaims.

TABLE 2 Sulfoximine/Urea

VEGFR2 VEGFR2 PDGFRβ Enzyme Cellular Enzyme Assay Assay Assay Example A(IC₅₀ nM) (IC₅₀ nM) (IC₅₀ nM) 1

8 20 20 2

3 25 17 3

8 3 17 4

42 68 73 5

6 11 21 6

6 5 27

TABLE 3 Ester/Urea

VEGFR2 VEGFR2 PDGFRβ Enzyme Cellular Enzyme Assay Assay Assay Example A(IC₅₀ nM) (IC₅₀ nM) (IC₅₀ nM) 7

7 22 11 8

10 12 24 9

15 63 45 10

17 27 15 11

20 328 18 12

21 355 26 13

45 941 12 14

81 1595 10 15

137 1352 28 16

NA NA 9

TABLE 4 Acid or Amide/Urea

VEGFR2 VEGFR2 PDGFRβ Enzyme Cellular Enzyme Assay Assay Assay Example YZ A (IC₅₀ nM) (IC₅₀ nM) (IC₅₀ nM) 17

41 N/A N/A 18

38 N/A N/A 19

120 N/A 431 20

35 N/A N/A 21

118 N/A N/A 22

132 N/A N/A

TABLE 5 Boronate Ester/Urea

VEGFR2 VEGFR2 PDGFRβ Enzyme Cellular Enzyme Assay Assay Assay Example A(IC₅₀ nM) (IC₅₀ nM) (IC₅₀ nM) 23

10 N/A 17 24

13 N/A N/A 25

16 N/A 21 26

25 N/A 10 27

37 N/A N/A 28

42 N/A 18 29

54 N/A 20 30

301 N/A 130

TABLE 6 Boronic Acid/Urea

VEGFR2 VEGFR2 PDGFRβ Enzyme Cellular Enzyme Assay Assay Assay Example A(IC₅₀ nM) (IC₅₀ nM) (IC₅₀ nM) 31

93 N/A 42 32

378 N/A 138

TABLE 7 Sulfoximine/Amide

VEGFR2 VEGFR2 PDGFRβ Enzyme Assay Cellular Assay Enzyme Assay Example Q(IC₅₀ nM) (IC₅₀ nM) (IC₅₀ nM) 33

17 6 457 34

32 277 36 35

50 45 258 36

51 N/A N/A 37

53 N/A 131 38

178 1023 128

TABLE 8 Ester/Amide

VEGFR2 VEGFR2 PDGFRβ Enzyme Cellular Enzyme Assay (IC₅₀ Assay (IC₅₀Assay (IC₅₀ Example Y Q nM) nM) nM) 39

31 75 61 40

57 145 25 41

199 1102 38 42

224 3945 503 43

264 2488 25 44

930 8722 29 45

N/A N/A 936 46 H

1171 5110 1278 47 H

1488 1815 N/A

TABLE 9 Reverse Amides

VEGFR2 VEGFR2 PDGFRβ Enzyme Cellular Enzyme Assay Assay Assay Example T(IC₅₀ nM) (IC₅₀ nM) (IC₅₀ nM) 48

3570 N/A >10,000

TABLE 10 Other Sulfoximine substituents/Ureas

VEGFR2 VEGFR2 PDGFRβ Enzyme Cellular Enzyme Assay Assay Assay Example YA (IC₅₀ nM) (IC₅₀ nM) (IC₅₀ nM) 53

5 N/A 16 54

3 N/A N/A 55

4 N/A N/A 56

8 N/A  8

TABLE 11 PKR data for Pyridyl Benzothiophenes PKR KINASEGLO Enzyme AssayIC50 Example Structure (nM) 5

 69 6

167

TABLE 12 VEGFR2 PKR Enzyme KINASEGLO Assay Enzyme Assay ExampleStructure (IC₅₀ nM) IC50 (nM) 57

 7 551 58

14 390

TABLE 13 VEGFR2 VEGFR2 PDGFRβ PDGFRβ Example Kinase Cellular KinaseCellular Number Structure IC₅₀ nM IC₅₀ nM IC₅₀ nM IC₅₀ nM 59

26 na 100 na 60

6 12 na na 61

25 na 58 150 62

53 na 24 na 63

206 na na na 64

57 10 na 66 65

99 35 82 118 66

115 25 na na 67

133 30 na na 68

891 na na na 69

13 na 83 na 70

14 3 138 173 71

33 13 88 141 72

42 11 13 192 73

9 14 na na 74

7 41 na na 75

7 74 na na 76

29 115 na na

What is claimed is:
 1. A compound selected from: 6-amino-N-[dimethyl(oxido)-λ⁴-sulfanylidene]-5-{5-[(3-methyl-2-furoyl)amino]-1-benzothien-2-yl}nicotinamide; methyl 6-amino-5-{5-[(3-methyl-2-furoyl)amino]-1-benzothien-2-yl}nicotinate; or a pharmaceutically acceptable salt thereof.
 2. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable adjuvant, diluent or carrier. 